Fused heterocyclic compounds

ABSTRACT

Certain fused pyrrole- and pyrazole-containing heterocyclic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are serotoninreceptor modulators. More particularly, there is provided by the presentinvention fused heterocyclic compounds that are serotonin receptormodulators useful for the treatment of disease states mediated byserotonin receptor activity.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmittereliciting effects via a multiplicity of receptors. To date, at leastfifteen different 5-HT receptors have been identified, largely as theresult of cloning cDNA's, and these receptors have been grouped intoseven families (5-HT₁ through 5-HT₇) (Hoyer, D. et al. Pharmacol.Biochem. Behav. (2002) 71, 533-554). Fourteen of the fifteen cloned 5-HTreceptors are expressed in the brain. 5-HT is implicated in many diseasestates, particularly conditions of the central nervous system including;depression, anxiety, schizophrenia, eating disorders, obsessivecompulsive disorder, learning and memory dysfunction, migraine, chronicpain, sensory perception, motor activity, temperature regulation,nociception, sexual behavior, hormone secretion and cognition. Theidentification of multiple 5-HT receptors has provided the opportunityto characterize existing therapeutic agents thought to act via theserotonergic system. Consequently, this has led to the realization thatmany drugs have non-selective properties (Roth, B. L. et al.Neuroscientist (2000) 6(4) 252-262). For example, the antipsychoticdrugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibitaffinities for multiple serotonin receptors in addition to otherfamilies of receptors. Similar behavior has been noted forantidepressants, including imipramine, nortriptaline, fluoxetine andsertraline. Similarly, the anti-migraine agent sumatriptan exhibits highaffinity for several serotonin receptors. While the lack of selectivityoften contributes to a favorable therapeutic outcome, it can also causeundesirable and dose-limiting side effects (Stahl, S. M. EssentialPsychopharmacology, 2^(nd) ed., Cambridge University Press, Cambridge,U.K., 2000). Thus, the inhibition of serotonin and norepinephrine uptaketogether with 5-HT₂ receptor blockade is responsible for the therapeuticeffects of the tricyclic antidepressants. In contrast, their blockade ofhistamine H₁, muscarinic and alpha-adrenergic receptors can lead tosedation, blurred vision and orthostatic hypertension respectively.Likewise, the atypical antipsychotics, including olanzapine andclozapine, are considered to have positive therapeutic effectsattributable to their actions at 5-HT₂, D₂ and 5-HT₇ receptors.Conversely, their side effect liability is due to their affinities at arange of dopaminergic, serotonergic and adrenergic receptors.

More selective ligands therefore have the potential to ameliorateuntoward pharmacologies and provide novel therapies. More importantlythe ability to obtain compounds with known receptor selectivitiesaffords the prospect to target multiple therapeutic mechanisms andimprove clinical responses with a single drug.

SUMMARY OF THE INVENTION

The invention features a compound of formulae (I), (II) and (III):

wherein

-   m is 0, 1 or 2;-   n is 1, 2 or 3;-   p is 1, 2 or 3, with the proviso that where m is 1, p is not 1;-   m+n is less than or equal to 4;-   m+p is less than or equal to 4;-   q is 0 or 1;-   r is 0, 1, 2, 3, 4, or 5;-   R³ is —C₁₋₄alkyl, allyl, propargyl, or benzyl, each optionally    substituted with —C₁₋₃alkyl, —OH, or halo;-   Ar is an aryl or heteroaryl ring selected from the group consisting    of:    -   a) phenyl, optionally mono-, di- or tri-substituted with R^(r)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO—,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)- or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(r) is selected from the group consisting of —OH,            —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₂₋₆alkenyl, —OC₃₋₆alkenyl,            —C₂₋₆alkynyl, —OC₃₋₆alkynyl, —CN, —NO₂, —N(R^(y))R^(z)            (wherein R^(y) and R^(z) are independently selected from H            or C₁₋₆alkyl), —(C═O)N(R^(y))R^(z), —(N—R^(t))COR^(t),            —(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t) is H or C₁₋₆alkyl),            —(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (wherein n is            selected from 0, 1 or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo,            —CF₃, —OCF₃, —COOH and —COOC₁₋₆alkyl;    -   b) phenyl or pyridyl fused at two adjacent carbon ring members        to a three membered hydrocarbon moiety to form a fused five        membered aromatic ring, which moiety has one carbon atom        replaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up        to one additional carbon atom optionally replaced by —N═, the        fused rings optionally mono-, di- or tri-substituted with R^(r);    -   c) phenyl fused at two adjacent ring members to a four membered        hydrocarbon moiety to form a fused six membered aromatic ring,        which moiety has one or two carbon atoms replaced by —N═, the        fused rings optionally mono-, di- or tri-substituted with R^(r);    -   d) naphthyl, optionally mono-, di- or tri-substituted with        R^(r);    -   e) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH or >N(C₁₋₄alkyl),        having up to one additional carbon atoms optionally replaced by        —N═, optionally mono- or di-substituted with R^(r) and        optionally benzofused or pyridofused at two adjacent carbon        atoms, where the benzofused or pyridofused moiety is optionally        mono-, di-, or tri-substituted with R^(r); and    -   f) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by —N═, optionally mono-        or di-substituted with R^(r) and optionally benzofused or        pyridofused at two adjacent carbon atoms, where the benzofused        or pyridofused moiety is optionally mono- or di-substituted with        R^(r);    -   g) phenyl or pyridyl, substituted with a substituent selected        from the group consisting of phenyl, pyridyl, thiophenyl,        oxazolyl and tetrazolyl, where the resultant substituted moiety        is optionally further mono-, di- or tri-substituted with R^(r);-   ALK is a branched or unbranched C₁₋₈alkylene, C₂₋₈alkenylene,    C₂₋₈alkynylene or C₃₋₈cycloalkenylene, optionally mono-, di-, or    tri-substituted with a substituent independently selected from the    group consisting of: —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,    —N(R^(a))R^(b) (wherein R^(a) and R^(b) are independently selected    from H, C₁₋₆alkyl or C₂₋₆alkenyl), —(C═O)N(R^(a))R^(b),    —(N—R^(c))COR^(c), —(N—R^(c))SO₂C₁₋₆alkyl (wherein R^(c) is H or    C₁₋₆alkyl), —(C═O)C₁₋₆alkyl, —(S═(O)_(d))—C₁₋₆alkyl (wherein d is    selected from 0, 1 or 2), —SO₂N(R^(a))R^(b), —SCF₃, halo, —CF₃,    —OCF₃, —COOH and —COOC₁₋₆alkyl;-   CYC is hydrogen or a carbocyclic, heterocyclic, aryl or heteroaryl    ring selected from the group consisting of:    -   i) phenyl, optionally mono-, di- or tri-substituted with R^(q)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO—,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)- or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(q) is selected from the group consisting of —OH,            —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl,            phenyl, —Ophenyl, benzyl, —Obenzyl, —CN, —NO₂,            —N(R^(a))R^(b) (wherein R^(a) and R^(b) are independently            selected from H, C₁₋₆alkyl or C₂₋₆alkenyl, or R^(a) and            R^(b) may be taken together with the nitrogen of attachment            to form an otherwise aliphatic hydrocarbon ring, said ring            having 5 to 7 members, optionally having one carbon replaced            with >O, ═N—, >NH or >N(C₁₋₄alkyl), optionally having one            carbon substituted with —OH, and optionally having one or            two unsaturated bonds in the ring), —(C═O)N(R^(a))R^(b),            —(N—R^(c))COR^(c), —(N—R^(c))SO₂C₁₋₆alkyl (wherein R^(c) is            H or C₁₋₆alkyl or two R^(c) in the same substituent may be            taken together with the amide of attachment to form an            otherwise aliphatic hydrocarbon ring, said ring having 4 to            6 members), —N—(SO₂C₁₋₆alkyl)₂, —(C═O)C₁₋₆alkyl,            —(S═(O)_(d))—C₁₋₆alkyl (wherein d is selected from 0, 1 or            2), —SO₂N(R^(a))R^(b), —SCF₃, halo, —CF₃, —OCF₃, —COOH and            —COOC₁₋₆alkyl;    -   ii) phenyl or pyridyl fused at two adjacent carbon ring members        to a three membered hydrocarbon moiety to form a fused five        membered aromatic ring, which moiety has one carbon atom        replaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up        to one additional carbon atom optionally replaced by —N═, the        fused rings optionally mono-, di- or tri-substituted with R^(q);    -   iii) phenyl fused at two adjacent carbon ring members to a four        membered hydrocarbon moiety to form a fused six membered        aromatic ring, which moiety has one or two carbon atoms replaced        by —N═, the fused rings optionally mono-, di- or tri-substituted        with R^(q);    -   iv) naphthyl, optionally mono-, di- or tri-substituted with        R^(q);    -   v) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH or >N(C₁₋₄alkyl),        having up to one additional carbon atoms optionally replaced by        —N═, optionally mono- or di-substituted with R^(q) and        optionally benzofused or pyridofused at two adjacent carbon        atoms, where the benzofused or pyridofused moiety is optionally        mono-, di-, or tri-substituted with R^(q);    -   vi) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by —N═, optionally mono-        or di-substituted with R^(q) and optionally benzofused or        pyridofused at two adjacent carbon atoms, where the benzofused        or pyridofused moiety is optionally mono- or di-substituted with        R^(q);    -   vii) a 3-8 membered non-aromatic carbocyclic or heterocyclic        ring said ring having 0, 1 or 2 non-adjacent heteroatom members        selected from O, S, —N═, >NH or >NR^(q), having 0, 1 or 2        unsaturated bonds, having 0, 1 or 2 carbon members which is a        carbonyl, optionally having one carbon member which forms a        bridge, having 0 to 5 substituents R^(q) and optionally        benzofused or pyridofused at two adjacent carbon atoms where the        benzofused or pyridofused moiety has 0, 1, 2 or 3 substituents        R^(q); and    -   viii) a 4-7 membered non-aromatic carbocyclic or heterocyclic        ring said ring having 0, 1 or 2 non-adjacent heteroatom members        selected from O, S, —N═, >NH or >NR^(q), having 0, 1 or 2        unsaturated bonds, having 0, 1 or 2 carbon members which is a        carbonyl and optionally having one carbon member which forms a        bridge, the heterocyclic ring fused at two adjacent carbon atoms        forming a saturated bond or an adjacent carbon and nitrogen atom        forming a saturated bond to a 4-7 membered carbocyclic or        heterocyclic ring, having 0 or 1 possibly additional heteroatom        member, not at the ring junction, selected from O, S, —N═, >NH        or >NR^(q), having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2        carbon members which is a carbonyl and the fused rings having 0        to 5 substituents R^(q);-   R¹ is selected from the group consisting of H, C₁₋₇alkyl,    C₂₋₇alkenyl, C₂₋₇alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₇alkyl,    C₃₋₇cycloalkenyl, C₃₋₇cycloalkenylC₁₋₇alkyl and    benzo-fusedC₄₋₇cycloalkyl, each optionally mono-, di-, or    tri-substituted with R^(p);    -   R^(p) is selected from the group consisting of —OH, —OC₁₋₆alkyl,        —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂, phenyl, pyridyl,        thienyl, furanyl, pyrrolyl, —N(R^(s))R^(u) (wherein R^(s) and        R^(u) are independently selected from H or C₁₋₆alkyl, or may be        taken together with the nitrogen of attachment to form an        otherwise aliphatic hydrocarbon ring, said ring having 5 to 7        members, optionally having one carbon replaced with >O, ═N—, >NH        or >N(C₁₋₄alkyl) and optionally having one or two unsaturated        bonds in the ring), —(C═O)N(R^(s))R^(u), —(N—R^(v))COR^(v),        —(N—R^(v))SO₂C₁₋₆alkyl (wherein R^(v) is H or C₁₋₆alkyl or two        R^(v) in the same substituent may be taken together with the        amide of attachment to form an otherwise aliphatic hydrocarbon        ring, said ring having 4 to 6 members), —(C═O)C₁₋₆alkyl,        —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1 or 2),        —SO₂N(R^(s))R^(u), —SCF₃, halo, —CF₃, —OCF₃, —COOH and        —COOC₁₋₆alkyl, wherein the foregoing phenyl, pyridyl, thienyl,        furanyl and pyrrolyl substituents are optionally mono-, di-, or        tri-substituted with a substituent independently selected from        the group consisting of: —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl, —CN,        —NO₂, —N(R^(a))R^(b) (wherein R^(a) and R^(b) are independently        selected from H, C₁₋₆alkyl or C₂₋₆alkenyl), —(C═O)N(R^(a))R^(b),        —(N—R^(c))COR^(c), —(N—R^(c))SO₂C₁₋₆alkyl (wherein R^(c) is H or        C₁₋₆alkyl), —(C═O)C₁₋₆alkyl, —(S═(O)_(d))—C₁₋₆alkyl (wherein d        is selected from 0, 1 or 2), —SO₂N(R^(a))R^(b), —SCF₃, halo,        —CF₃, —OCF₃, —COOH and —COOC₁₋₆alkyl;-   R² is selected from the group consisting of H, C₁₋₇alkyl,    C₂₋₇alkenyl, C₂₋₇alkynyl and C₃₋₇cycloalkyl;-   and enantiomers, diastereomers, hydrates, solvates and    pharmaceutically acceptable salts, esters and amides thereof.

Similarly, isomeric forms of the compounds of formulae (I), (II), and(III), and of their pharmaceutically acceptable salts, esters, andamides, are encompassed within the present invention, and referenceherein to one of such isomeric forms is meant to refer to at least oneof such isomeric forms. One of ordinary skill in the art will recognizethat compounds according to this invention may exist, for example in asingle isomeric form whereas other compounds may exist in the form of aregioisomeric mixture.

The invention also features pharmaceutical compositions containing suchcompounds and methods of using such compositions in the treatment orprevention of disease states mediated by the serotonin receptors,particularly, 5-HT₇ and/or 5-HT₂ receptor subtypes.

DETAILED DESCRIPTION

Preferably, m is 1 or 2 and most preferably, m is 1.

Preferably, n is 1 or 2.

Preferably, p is 1 or 2.

Preferably, m+n is 2 or 3.

Preferably, m+p is 2 or 3.

Preferably, q is 1.

Preferably, r is 0, 1, or 2.

Preferably, r is 4.

Preferably R³, optionally substituted, is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, allyl, propargyl,and benzyl.

Preferably, R³ is methyl.

Preferably Ar, optionally substituted, is selected from the groupconsisting of:

a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,

b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-,5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4,5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,

c) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7-or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,

d) naphthyl,

e) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl,2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl,2-benzimidazolyl, 3-indazolyl,

f) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl,1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2- or 3-quinoxalinyl,2- or 4-quinazolinyl, [1,5], [1,6], [1,7], or [1,8]naphthyridin-2-, 3-,or 4-yl, [2,5], [2,6], [2,7], [2,8]naphthyridin-1-, 3-, or 4-yl, and

g) biphenyl, 4-tetrazolylphenyl.

More preferably, Ar, optionally substituted, is selected from the groupconsisting of phenyl, pyridyl, thiophen-2-yl and thiophen-3-yl.

Specific Ar may be selected from the group consisting of phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl,4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxol-4 or5-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-dimethylaminophenyl,4-carbamoylphenyl, 4-fluoro-3-methylphenyl, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl,5-methylthiophen-2-yl, 5-chlorothiophen-3-yl, 5-methylthiophen-3-yl,4′-chlorobiphenyl, and 4-tetrazolylphenyl.

Preferably, ALK, optionally substituted, is selected from the groupconsisting of methylene, ethylene, propylene, butylene, tert-butylene,pentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene,isopropylene, but-3-enylene, isobutylene, 3-methylbutylene, allylene,and prop-2-ynylene.

Specific ALK may be selected from the group consisting of methylene,trifluoromethylmethylene, methoxycarbonylmethyl, methylcarbamoylmethyl,ethylene, propylene, 3-methoxycarbonyl propylene, 3-carboxy propylene,butylene, tert-butylene, 4-hydroxybutylene, 4-methoxycarbonyl butylene,4-carboxy butylene, pentylene, 5-hydroxypentylene, 1-ethylpropylene,2-ethylpropylene, 2-ethylbutylene, isopropylene, but-3-enylene,isobutylene, 3-methylbutylene, prop-2-ynylene, 2-dimethylaminoethylene,and 2-cyanoethylene.

Preferably CYC, optionally substituted, is hydrogen or is selected fromthe group consisting of:

i) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,

ii) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-,5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4,5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,

iii) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-,7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,

iv) naphthyl,

v) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl,2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl,2-benzimidazolyl, 3-indazolyl,

vi) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl,1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2- or 3-quinoxalinyl,2- or 4-quinazolinyl, [1,5], [1,6], [1,7], or [1,8]naphthyridin-2-, 3-,or 4-yl, [2,5], [2,6], [2,7], [2,8]naphthyridin-1-, 3-, or 4-yl,

vii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cyclooctyl, adamantyl, pyrrolinyl, pyrrolidinyl,pyrazolinyl, piperidinyl, homopiperidinyl, azepanyl, tetrahydrofuranyl,tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl,piperidinonyl, indanyl, dihydroindolyl, oxindolyl,dihydropyrrolopyridinyl, and

viii) bicyclo[4.1.0]heptane, octahydroindolyl, octahydroisoindolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydropyrrolopyridinyl,and octahydropyrrolopyrrolidinyl.

More preferably, CYC, optionally substituted, is selected from the groupconsisting of hydrogen, phenyl, indolyl, benzthiazolyl, isoquinolyl,quinazolinyl, naphthalen-1 or 2-yl, thiophen-2-yl, thiophen-3-yl,furan-2-yl, furan-3-yl, pyridinyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, piperidin-2,3 or 4-yl, 2-pyrrolin-2, 3, 4 or5-yl, 3-pyrrolin-2 or 3-yl, 2-pyrazolin-3, 4 or 5-yl, morpholin-2, 3, 5or 6-yl, thiomorpholin-2, 3, 5 or 6-yl, piperazin-2, 3, 5 or 6-yl,pyrrolidin-2 or 3-yl, homopiperidinyl, adamantanyl, andoctahydroindolyl.

Most preferably, CYC, optionally substituted, is selected from the groupconsisting of hydrogen, phenyl, pyridyl, cyclobutyl, cyclopentyl,cyclohexyl, thiophen-2-yl, thiophen-3-yl, tetrahydropyranyl, furan-2-yl,furan-3-yl and naphthalen-1 or 2-yl.

Specific CYC may be selected from the group consisting of hydrogen,phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl,2,6-dimethylphenyl, 2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl,3,4,5-trimethoxyphenyl, cyclobutyl, cyclohexyl, cyclopentyl,4-fluoro-3-methylphenyl, 3-nitrophenyl, 4-nitrophenyl,4-methyl-3-fluorophenyl, 3,4-dimethylphenyl, 4-methoxy-3-fluorophenyl,4-methoxy-2-methylphenyl, 3-aminophenyl, 4-aminophenyl,4-carbomethoxyphenyl, 3-methanesulfonylamino-phenyl,4-methanesulfonylamino-phenyl, 3-dimethanesulfonylamino-phenyl,4-dimethanesulfonylamino-phenyl, thiophen-2-yl, thiophen-3-yl,5-chlorothiophen-2-yl, benzo[1,3]dioxol-4 or 5-yl, tetrahydropyran-2,3or 4-yl, furan-2-yl, furan-3-yl, 5-carboxyethyl-furan-2-yl, naphthalen-1or 2-yl, 3,4-bisbenzyloxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl and3,4-dihydroxyphenyl.

Preferably, R¹ is selected from the group consisting of hydrogen,C₁₋₃alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl, C₅₋₆cycloalkenyl, benzo-fusedC₅₋₆cycloalkyl,each optionally mono-, di-, or tri-substituted with R^(p).

More preferably, R¹, optionally R^(p) substituted, is selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.

Specific R¹ may be selected from the group consisting of hydrogen,methyl, ethyl, propyl, isopropyl, 3-hydroxypropyl, benzyl,3,4-dimethoxybenzyl, methoxycarbonylmethyl, carbamoylmethyl, phenethyl,phenpropyl, and hydroxyethyl.

Preferably, R² is hydrogen, C₁₋₃alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, orC₃₋₆cycloalkyl.

More preferably, R² is hydrogen or methyl.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical, includingstereoisomers and racemic mixtures, diastereomers, and geometric isomersthat possess the activity that characterizes the compounds of thisinvention. In addition, certain compounds referred to herein can existin solvated as well as unsolvated forms. It is understood that thisinvention encompasses all such solvated and unsolvated forms thatpossess the activity that characterizes the compounds of this invention.

Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. The compounds of the present invention may be labeledwith radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, and the like foruse in imaging or for radioactive treatment of patients. An example ofsuch compounds is an isotopically labeled compound, such as an ¹⁸Fisotopically labeled compound that may be used as a probe in detectionand/or imaging techniques, such as positron emission tomography (PET)and single-photon emission computed tomography (SPECT). Preferably,compounds of the present invention labeled with ¹⁸F or ¹¹C may be usedas a positron emission tomography (PET) molecular probe for studyingserotonin-mediated disorders. Another example of such compounds is anisotopically labeled compound, such as a deuterium and/or tritiumlabeled compound that may be used in reaction kinetic studies. Thecompounds described herein may be reacted with an appropriatefunctionalized radioactive reagents using conventional chemistry toprovide radiolabeled compounds.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈alkyl, C₃₋₈cycloalkyl, aryl,C₂₋₁₀heteroaryl, or C₂₋₁₀ non-aromatic heterocyclic), amino additionsalts, acid addition salts, esters, and amides that are within areasonable benefit/risk ratio, pharmacologically effective and suitablefor contact with the tissues of patients without undue toxicity,irritation, or allergic response. Representative addition salts forcompounds of formula (I) displaying basic functionality includehydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. Representative addition salts forcompounds of formula (I) displaying acidic functionality are those thatform non-toxic base salts with such compounds. These salts may includealkali metal and alkali earth cations such as sodium, potassium,calcium, and magnesium, as well as non-toxic ammonium, quaternaryammonium, and amine cations such as tetramethyl ammonium, methylamine,trimethylamine, and ethylamine. See example, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66:1-19, which isincorporated herein by reference.

Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di(C₁₋₂alkyl)amines. Representative pharmaceuticallyacceptable esters of the invention include C₁₋₇alkyl, C₆₋₇cycloalkyl,phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred esters include methylesters.

Preferred compounds, which are fused pyrroles, are selected from thegroup consisting of:

EX CHEMICAL NAME 11-Benzyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 21-Benzyl-3-(3-chloro-4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 34-(1-Benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)- phenol; 41-Benzyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 51-Benzyl-3-(5-chloro-thiophen-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 61-Benzyl-3-thiophen-2-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2- c]pyridine;7 1-(3-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 81-Benzyl-3-(3-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 93-(4-Chloro-phenyl)-1-(2-fluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 101-(3-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 111-(2-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 121-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 131-Benzyl-3-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 141-(4-Methoxy-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 151-(2-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 161-(2,4-Dichloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 171-Benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 181-Benzyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 191-Benzyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 203-Benzo[1,3]dioxol-5-yl-1-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 211-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 221-Butyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 231-Benzyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 241-Benzyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 251-Benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 261-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine; 271-Benzyl-3-(5-methyl-thiophen-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 281-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine; 29 1-Benzyl-3-(5-chloro-thiophen-2-yl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine; 301-(4-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 311-Benzyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 321-Benzyl-3-(3-chloro-phenyl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine; 331-Benzyl-3-(3-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 341-Benzyl-3-(4-methoxy-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 351-Benzyl-3-(4-chloro-phenyl)-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 361-Benzyl-3-(4-chloro-phenyl)-5-isopropyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 373-[1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl]-propan-1-ol; 381-Benzyl-3-(4-chloro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 391-Benzyl-3-(3-chloro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 401-Benzyl-3-(3-chloro-4-fluoro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 411,5-Dibenzyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; and42 1-Benzyl-5-isopropyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

Preferred compounds, which are fused 1-substituted pyrazoles, areselected from the group consisting of:

EX CHEMICAL NAME 431-Benzyl-3-(4-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 441-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 451-Benzyl-3-(2-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 461-Benzyl-3-(3-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 471-Benzyl-3-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 481-Benzyl-3-(2,3-difluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 491-Benzyl-3-(3,4-dichloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 501-[4-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-ethanone; 511-Benzyl-3-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 521-Benzyl-3-(3-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 53 3-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 544-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 551-(4-Chloro-benzyl)-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 561-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 571-Benzyl-3-phenyl-6-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;58 1-Benzyl-6-isopropyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 591-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 601-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; 613-(4-Chloro-phenyl)-1-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 633-(4-Chloro-phenyl)-1-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;65 3-(4-Chloro-phenyl)-1-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 671-Butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;69 3-(4-Chloro-phenyl)-1-(2-cyclohexyl-ethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 713-(4-Chloro-phenyl)-1-phenethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 733-(4-Chloro-phenyl)-1-(4-fluoro-3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 743-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 753-(4-Chloro-phenyl)-1-(4-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 763-(4-Chloro-phenyl)-1-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 773-(4-Chloro-phenyl)-1-(4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 783-(4-Chloro-phenyl)-1-(3,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 793-(4-Chloro-phenyl)-1-(3-nitro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 803-(4-Chloro-phenyl)-1-(3-fluoro-4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 813-(4-Chloro-phenyl)-1-(3,4-dimethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 855-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoic acid methyl ester; 865-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoic acid; 875-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentan-1-ol; 884-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyric acid methyl ester; 914-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyric acid; 934-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butan-1-ol; 963-(4-Chloro-phenyl)-1-(3-fluoro-4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 983-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 994-(3-Phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenylamine; 100N-[4-(3-Phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-methanesulfonamide; 101N,N-[4-(3-phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-dimethanesulfonamide; 1021-Benzyl-3-p-tolyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1033-(4-Chloro-phenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1041-Benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;105 3-(4-Chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1063-(4-Chloro-phenyl)-1-(2-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1073-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1083-(4-Chloro-phenyl)-1-(2,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1093-(4-Chloro-phenyl)-1-(2-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1101-(2-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1111-But-3-enyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1121-(2-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1131-(4-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1143-(4-Chloro-phenyl)-1-(2-ethyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1153-(4-Chloro-phenyl)-1-(5-chloro-thiophen-2-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1161-(3-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1173-(4-Chloro-phenyl)-1-cyclohexylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1183-(4-Chloro-phenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1191-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1203-(4-Chloro-phenyl)-1-(tetrahydro-pyran-4-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1213-(4-Chloro-phenyl)-1-(2,6-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1233-(4-Chloro-phenyl)-1-(4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1243-(4-Chloro-phenyl)-1-(3-methyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1253-(4-Chloro-phenyl)-1-(2-trifluoromethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene 1283-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1343-(4-Chloro-phenyl)-1-prop-2-ynyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1353-(4-Chloro-phenyl)-1-pentafluorophenylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1373-(4-Chloro-phenyl)-1-(2,4,6-trifluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1382-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzonitrile; 1423-(4-Chloro-phenyl)-1-naphthalen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1445-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-furan-2-carboxylic acid ethyl ester; 1453-(4-Chloro-phenyl)-1-naphthalen-1-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 147[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-acetic acid methyl ester; 1482-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-N-methyl-acetamide; 1503-(4-Chloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1523-(4-Chloro-phenyl)-1-(2,6-dimethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1541-(3,4-Bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1563-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol; 1574-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol; 1584-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-3-methyl-phenol; 1594-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzene-1,2-diol; 1604-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluoro-phenol; 1622-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol; 1651-Benzyl-3-(4-chloro-phenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1661-Benzyl-3-(4-chloro-phenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1673-(4-Chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1681-Butyl-3-(4-chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1691-Benzyl-3-(4-chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 170[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetic acid methyl ester; 1712-[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-ethanol; 1723-(4-Chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1733-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,6-triaza-cyclopentacyclooctene; 1743-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,7-triaza-cyclopentacyclooctene; 1753-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; 230{4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenyl}-methyl-amine; 2373-(4-Chloro-phenyl)-1-cyclobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2393-(4-Chloro-phenyl)-1-cyclohexyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2543-(4-Chloro-phenyl)-1-cycloheptyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2553-(4-Chloro-phenyl)-1-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2731-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza- azulenecitrate salt; 3163-(4-Chloro-phenyl)-1-pyridin-4-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3173-(4-Chloro-phenyl)-1-pyridin-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3193-(4-Chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3204-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzoic acid methyl ester; 3213-(4-Chloro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3223-(4-Chloro-phenyl)-1-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 323{2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-ethyl}-dimethyl-amine. 3243-(4-Chloro-phenyl)-1-(1-oxy-pyridin-2-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3252-[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetamide; 3263-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-propionitrile. 3321-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; 3333-(4-Chloro-phenyl)-1-(4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; 3343-(4-Chloro-phenyl)-1-(3,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; 3353-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; 3363-(4-Chloro-phenyl)-1-(3-fluoro-4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; and 3373-(4-Chloro-phenyl)-1-(4-fluoro-3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene.

Preferred compounds, which are fused 2-substituted pyrazoles, areselected from the group consisting of:

EX CHEMICAL NAME 623-(4-Chloro-phenyl)-2-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 643-(4-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;66 3-(4-Chloro-phenyl)-2-propyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 682-Butyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;70 3-(4-Chloro-phenyl)-2-(2-cyclohexyl-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 723-(4-Chloro-phenyl)-2-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 825-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester; 835-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid; 845-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentan-1-ol; 894-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyric acid methyl ester; 904-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyric acid; 924-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butan-1-ol; 943-(4-Chloro-phenyl)-2-(3,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 953-(4-Chloro-phenyl)-2-(4-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 973-(4-Chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1223-(4-Chloro-phenyl)-2-cyclohexylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1263-(4-Chloro-phenyl)-2-(2-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1272-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1293-(4-Chloro-phenyl)-2-(2,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1305-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-furan-2-carboxylic acid ethyl ester; 1313-(4-Chloro-phenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1323-(4-Chloro-phenyl)-2-(2-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1332-Benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1363-(4-Chloro-phenyl)-2-thiophen-2-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1393-(4-Chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1403-(4-Chloro-phenyl)-2-(2,6-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1413-(4-Chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1433-(4-Chloro-phenyl)-2-(2-ethyl-butyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1462-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1493-(4-Chloro-phenyl)-2-pentafluorophenylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1513-(4-Chloro-phenyl)-2-naphthalen-1-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1533-(4-Chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1552-(3,4-Bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1614-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-2-fluoro-phenol; 1634-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-3-methyl-phenol; 1642-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-phenol; 1762,3-Diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1772-Cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1783-(4-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1792-Cyclohexyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1802-Cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1813-(4-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1822-Cyclopentyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1832-(1-Ethyl-propyl)-3-(3-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1842-(1-Ethyl-propyl)-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1852-(1-Ethyl-propyl)-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1862-(1-Ethyl-propyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;187 3-(4-Chloro-phenyl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1882-(2,2,2-Trifluoro-ethyl)-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1892-Isopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1903-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1912-(1-Ethyl-propyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1922-Cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1932-Ethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1942-Ethyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;195 2-Ethyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;196 2-(3-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1972-(3-Fluoro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1982-(2-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1992-Phenyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;200 3-(4-Fluoro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2013-(4-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2023-(3-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2032-Phenyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2042,3-Diphenyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine; 2053-Phenyl-2-(3-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2063-(4-Methoxy-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2072-(4-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2086-Methyl-2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2092-Isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2103-(4-Ethyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2113-(4-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2124-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 2132-Isopropyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2142-Ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2152-tert-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2162-tert-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2172-Cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2182-Cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2193-(3-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2202-Cyclopentyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2212-(3,3-Dimethyl-cyclopentyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2222-(3,3-Dimethyl-cyclopentyl)-3-(4-fluoro-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2233-(4-Chloro-phenyl)-2-(3,3-dimethyl-cyclopentyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2242-Cyclohexyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2252-Cyclohexyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2262-Cyclohexyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2272-Cyclohexyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2284-(2-Cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 2293-(3-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2313-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine; 2322-Cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;233 2-Cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2342-tert-Butyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2352-tert-Butyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;236 2-Cyclopentyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2383-(4-Chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2402-tert-Butyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2413-(3-Chloro-4-fluoro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2422-Isopropyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2432-Isopropyl-3-(4-trifluoromethoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2442-Isopropyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2453-(4-tert-Butyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2462-Isopropyl-3-m-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2472-Isopropyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2483-(3,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2492-Benzyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2502-Isopropyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;251 3-(2-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2521-[4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-ethanone; 2532-Isopropyl-3-(4-nitro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2562-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene; 2572-Ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;258 4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 2593-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2603-(4-Fluoro-phenyl)-2,6-diisopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2612-Ethyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2622-Ethyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2632-Ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2642-Ethyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2653-(2-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;266 2-Ethyl-3-(2-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2673-(2,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 268[4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-dimethyl-amine; 2696-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2703-(4-Fluoro-phenyl)-2-isopropyl-6-(3-phenyl-propyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2713-(4-Fluoro-phenyl)-2-isopropyl-6-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and 2723-(4-Fluoro-phenyl)-2-isopropyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. 2743-(4′-Chloro-biphenyl-4-yl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2753-(4′-Chloro-biphenyl-4-yl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2762-Cyclobutyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2772-Cyclobutyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2782-Cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2792-Cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2804-(2-Cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile 2812-Cyclopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2822-Cyclopropyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2832-(1-Ethyl-propyl)-3-(4-fluoro-3-methyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2842-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2852-Cyclopropyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2864-(2-Cyclopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 2876-Benzyl-2-isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine; 2882-Isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine; 2896-Benzyl-2-isopropyl-3-thiophen-3-yl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine; 2906-Benzyl-2-isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine. 2916-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine; 2923-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine; 2932-Isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine; 2942-Cyclopentyl-3-(4-fluoro-phenyl)-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2952-Cyclopentyl-5,5,7,7-tetramethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2962-Isopropyl-5,5,7,7-tetramethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2973-(4-Fluoro-phenyl)-2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2982-sec-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2992-sec-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3002-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3012-sec-Butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3022-Cyclopentyl-3-(4-fluoro-phenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3034-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzamide; 3042-Isopropyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3056-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3063-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3073-(4-Fluoro-phenyl)-2-isopropyl-4-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3082-Cyclopentyl-3-(4-fluoro-phenyl)-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3092-Cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3102-Cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3112-Isopropyl-7-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3122-Isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3133-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3143-(4-Fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3152-Isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3183-(4-Chloro-phenyl)-2-pyridin-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3273-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-propionitrile; 3283-(4-Chloro-phenyl)-2-cycloheptyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3293-(4-Chloro-phenyl)-2-cyclooctyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3303-(4-Chloro-phenyl)-2-(4-methyl-cyclohexyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3312-Benzyl-3-(4-chloro-phenyl)-2,4,5,6-tetrahydro-pyrrolo[3,4- c]pyrazole;and 338 3-(4-Fluoro-phenyl)-2-isopropyl-5,7-dimethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

In another embodiment of the present invention, preferred compounds areselected from the group consisting of:

EX CHEMICAL NAME 591-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 743-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 753-(4-Chloro-phenyl)-1-(4-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 763-(4-Chloro-phenyl)-1-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1033-(4-Chloro-phenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1041-Benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;108 3-(4-Chloro-phenyl)-1-(2,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1604-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluoro-phenol; 1651-Benzyl-3-(4-chloro-phenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1661-Benzyl-3-(4-chloro-phenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2142-Ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2572-Ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;and 273 1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene citrate salt.

In still another embodiment of the present invention, preferredcompounds are selected from the group consisting of:

EX CHEMICAL NAME 1313-(4-Chloro-phenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1332-Benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1772-Cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1783-(4-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1813-(4-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1822-Cyclopentyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1832-(1-Ethyl-propyl)-3-(3-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1842-(1-Ethyl-propyl)-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1862-(1-Ethyl-propyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;191 2-(1-Ethyl-propyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2152-tert-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2162-tert-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2172-Cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene; 2182-Cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2202-Cyclopentyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2362-Cyclopentyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2383-(4-Chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2413-(3-Chloro-4-fluoro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2422-Isopropyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2772-Cyclobutyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2782-Cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2792-Cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2842-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene; 3002-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3022-Cyclopentyl-3-(4-fluoro-phenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 3063-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and 3102-Cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

In yet another embodiment of the present invention preferred compoundsare selected from the group consisting of:

EX CHEMICAL NAME 471-Benzyl-3-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 643-(4-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;118 3-(4-Chloro-phenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1802-Cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene; 1903-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 1922-Cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2092-Isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2103-(4-Ethyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2113-(4-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2124-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 2132-Isopropyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 2322-Cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene;233 2-Cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 284 2-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 300 2-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and 3152-Isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety.

The fused heterocyclic compounds of formulas (I), (II), and (III) may beprepared by a number of reaction schemes. Access to compounds of formula(I) is described in Scheme 1. Preparation of compounds of formula (II)is described in Schemes 2, 3, 5, and 6. Synthesis of compounds offormula (III) is shown in Schemes 3 and 4. Persons skilled in the artwill recognize that certain compounds are more advantageously producedby one scheme as compared to the other.

Referring to Scheme 1, compounds of formula (I) may be prepared fromcompounds of formula (IV). The amine moiety in compounds of formula (IV)can be suitably protected, shown by substituent G, as an alkyl or benzylamine, amide, carbamate or other groups such as those described in“Protecting Groups In Organic Synthesis”, 3^(rd) ed.; T. W. Greene andP. G. M. Wuts, John Wiley & Sons, 1999 (G is —C₁₋₆alkyl, —COOC₁₋₆alkyl,—(C═O)C₁₋₆alkyl, or benzyl unsubstituted or substituted with —OC₁₋₆alkylor —C₁₋₆alkyl). A preferred protecting group would be the t-butylcarbamate (Boc) group. The carbonyl functional group of compound (IV)can be treated with a primary amine of type (V), in a suitable solventlike THF, toluene, benzene, methanol or ethanol at temperatures between20 and 110° C. with removal of water by either Dean-Stark apparatus orby the addition of a dehydrating agent such as SiO₂, MgSO₄, CuSO₄,Ti(O-iPr)₄ or 4 Å molecular sieves to form the corresponding imines oftype (VI). Preferred solvents are toluene and ethanol with preferreddehydrating agents being SiO₂ and 4 Å molecular sieves. One skilled inthe art would recognize that the imines of type (VI) might exist as morethan one tautomeric form. Compounds of type (VI) can then be treatedwith a nitro olefin of type (VII) to give pyrrole compounds of formula(VIII). One skilled in the art would recognize that imines of formula(VI), existing as more that one enamine tautomer, would give rise toregioisomers upon treatment with a nitro olefin of type (VII) dependingon the structure of the compound of formula (IV). The protecting groupon the nitrogen can either be removed using generally accepted methodsor, depending on the type of group involved, can be converted directlyto compounds of formula (I). More specifically, a group such as at-butyl carbamate can be removed with an acid like trifluoroacetic acidor hydrochloric acid and the like in a solvent such as CH₂Cl₂, ethanolor methanol to afford compounds of formula (IX). It will be generallyrecognized that compounds of formula (IX) represent a subset ofcompounds of formula (I) wherein R¹ is equal to H. Compounds of formula(IX) and (I) may be converted to their corresponding salts using methodsknown to those skilled in the art.

Compounds such as (I) can be prepared from compounds of type (IX) usingconventional synthetic methods such as alkylation or reductiveamination. Thus, treatment of compounds of formula (IX) with a compoundof formula (X) containing a carbonyl group in the presence of areductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in thepresence of a catalyst in a solvent such as CH₂Cl₂, DCE, THF, ethanol,methanol or similar will afford compounds of formula (I). One skilled inthe art will recognize that the addition of acid to decrease the pH ofthe reaction mixture to less than pH 7 may be required. Examples ofacids may include AcOH, Ti(O-iPr)₄, trifluoroacetic acid or hydrochloricacid and the like. In addition, compounds such as (IX) can be treatedwith an alkylating agent of type (XI). For example, treatment with analkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl,Br, I, OMs, OTs, or the like) in solvent such as DMF, DMA, THF orethanol and in the presence of a base like NaHCO₃, Na₂CO₃, K₂CO₃ orCs₂CO₃ will give compounds of formula (I).

Referring to Scheme 2, compounds of formula (II) can be prepared fromcompounds of formula (XII). As in Scheme 1, the amine moiety incompounds of formula (XII) can be suitably protected, shown bysubstituent G, as an alkyl or benzyl amine, amide, carbamate or othergroups such as those described in “Protecting Groups In OrganicSynthesis”, 3^(rd) ed.; T. W. Greene and P. G. M. Wuts, John Wiley &Sons, 1999. A preferred protecting group would be the t-butyl carbamate(Boc) group. The condensation of hydrazine with compounds of formula(XII) in a solvent like methanol, ethanol, isopropanol or t-butylalcohol at temperatures from 20 to 80° C. will form compounds of type(XIII). One skilled it the art will recognize that compounds of formula(XIII) may exist in more that one resonance form. More specifically,compounds of formula (XIII) are tautomeric with the corresponding3-hydroxypyrazoles. Compounds such as (XIII) can be treated with analkylating agent such as formula (XIV) to afford compounds of type (XV).For example, treatment with an alkyl or benzyl chloride, bromide,iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs, or thelike) in DMF, DMA, THF or ethanol in the presence of a base like NaHCO₃,Na₂CO₃, K₂CO₃, NaH, potassium tert-butoxide, or Cs₂CO₃ will affordcompounds of formula (XV). One skilled in the art will recognize thatthe alkylation of compounds of formula (XIII) may give rise toregioisomers. Compounds of type (XV) can be converted into a precursorfor transition metal-catalyzed cross-coupling reactions, such as Stille,Suzuki, Negishi or other such coupling reactions known to one skilled inthe art. For example, treatment with POCl₃, PCl₃, PCl₅, PBr₃ or POBr₃can afford the corresponding 3-halopyrazoles. A preferred method wouldinvolve treatment with a triflating agent such astrifluoromethanesulfonic anhydride orN-phenyltrifluoromethanesulfonimide in DCE, CH₂Cl₂, THF or the like inthe presence of a base like pyridine, triethylamine ordiisopropylethylamine to provide pyrazole triflates of formula (XVI).Treatment of triflates of formula (XVI) with an organoboron compound offormula (XVII) in the presence of a catalyst like Pd(PPh₃)₄,PdCl₂(PPh₃)₂, PdCl₂(Po-tol₃)₂, PdCl₂(dppe) or PdCl₂(dppf) in a solventsuch as THF, 1,4-dioxane, DMA, DMF, DME, toluene, toluene/ethanol, ortoluene/H₂O mixtures, in the presence of a base such as Na₂CO₃, K₂CO₃,Cs₂CO₃, K₃PO₄, KF, CsF, KOAc or the like will afford compounds offormula (XVIII). Preferred catalysts are Pd(PPh₃)₄ and PdCl₂(dppf), withor without additives such as dppf and catalytic Bu₄NBr. Preferredsolvents include THF, 1,4-dioxane, toluene, and toluene/H₂O mixtureswith preferred bases being Na₂CO₃, K₂CO₃, Cs₂CO₃, and K₃PO₄. Theprotecting group on the nitrogen of compounds of formula (XVIII) may beremoved using generally accepted methods, which one skilled in the artwould recognize. More specifically, a group such as a t-butyl carbamatecan be removed with an acid like trifluoroacetic acid or hydrochloricacid and the like in a solvent such as CH₂Cl₂, ethanol or methanol toafford compounds of formula (XIX). Compounds of formula (XIX) or (II)may be converted to their corresponding salts using methods known tothose skilled in the art. For example, amines of formula (XIX) can betreated with citric acid in a solvent such as methanol to provide thecorresponding citrate salt. It will be generally recognized thatcompounds of formula (XIX) represent a subset of compounds of formula(II) wherein R¹ is equal to H.

Compounds such as (II) can be prepared from compounds of type (XIX)using conventional synthetic methods such as alkylation or reductiveamination. Thus, treatment of compounds of formula (XIX) with a compoundof formula (X) containing a carbonyl group in the presence of areductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in thepresence of a catalyst in a solvent such as CH₂Cl₂, DCE, THF, ethanol,methanol or similar will afford compounds of formula (II). One skilledin the art will recognize that the addition of acid to decrease the pHof the reaction mixture to less than pH 7 may be required. Examples ofacids may include AcOH, Ti(O-iPr)₄, trifluoroacetic acid or hydrochloricacid and the like. In addition, compounds such as (XIX) can be treatedwith an alkylating agent of type (XI). For example, treatment with analkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl,Br, I, OMs, OTs, or the like) in solvent such as DMF, DMA, THF orethanol and in the presence of a base like NaHCO₃, Na₂CO₃, K₂CO₃ orCs₂CO₃ will give compounds of formula (II).

Referring to Scheme 3, compounds of formula (II), (Ill), (XXVII), and(XXVIII) can be prepared as described. The amine moiety in compounds offormula (XX) can be suitably protected, shown by substituent G, as analkyl or benzyl amine, amide, carbamate or other groups such as thosedescribed in “Protecting Groups In Organic Synthesis”, 3^(rd) ed.; T. W.Greene and P. G. M. Wuts, John Wiley & Sons, 1999. A preferredprotecting group would be the t-butyl carbamate (Boc) group. Thecarbonyl functional group of compound (XX) can be treated with asaturated secondary amine, such as morpholine, in a suitable solventlike toluene or benzene at temperatures between 20 and 110° C. withremoval of water by a Dean-Stark apparatus with or without an acidcatalyst such as TsOH, will afford the corresponding enamines of type(XXI). One skilled in the art would recognize that enamines of type(XXI) might exist as more that one enamine regioisomer depending on thestructure of the compound of formula (XX). Treatment of enamines (XXI)with a benzoyl chloride will afford the diketone compounds of formula(XXIV). Additionally, the carbonyl functional group of compound (XX) canbe treated with a diazoketone in the presence of a Lewis acid, such asBF₃, to give the diketone compounds (XXIV) directly. The condensation ofhydrazine with compounds of formula (XXIV) in a solvent like methanol,ethanol, isopropanol or t-butyl alcohol at temperatures from 20 to 80°C. will form pyrazole compounds of type (XXV). Compounds such as (XXV)can be treated with an alkylating agent of formula (XIV). For example,treatment with an alkyl or benzyl chloride, bromide, iodide, mesylate ortosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in DMF, DMA, THFor ethanol in the presence of a base like NaHCO₃, Na₂CO₃, NaH, potassiumtert-butoxide, K₂CO₃ or Cs₂CO₃ will afford a mixture of compounds offormula (XXVI) and (XVIII). One skilled in art would recognize that amixture of compounds of formula (XXVI) and (XVIII) may be separated bychromatographic or crystallization techniques. The protecting group onthe nitrogen may be removed using generally accepted methods, which oneskilled in the art would recognize. More specifically, a group such as at-butyl carbamate can be removed from compounds of formula (XXVI) and(XVIII) with an acid like trifluoroacetic acid or hydrochloric acid andthe like in a solvent such as CH₂Cl₂, ethanol or methanol to affordcompounds of formula (XXVII) and (XIX) respectively. Compounds offormula (XXVII), (XIX), (II), or (III) may be converted to theircorresponding salts using methods known to those skilled in the art. Itwill be generally recognized that compounds of formula (XXVII) and (XIX)represent subsets of compounds of formula (III) and (II) respectively,wherein R¹ is equal to H.

Compounds such as (II) and (III) can be prepared from compounds offormula (XIX) and (XXVII) respectively, using conventional syntheticmethods such as alkylation or reductive amination. Thus, treatment ofcompounds of formula (XIX) with a compound of formula (X) containing acarbonyl group in the presence of a reductant such as NaBH₄, NaBH₃CN,NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solventsuch as CH₂Cl₂, DCE, THF, ethanol, methanol or similar will affordcompounds of formula (II). One skilled in the art will recognize thatthe addition of acid to decrease the pH of the reaction mixture to lessthan pH 7 may be required. Examples of acids may include AcOH,Ti(O-iPr)₄, trifluoroacetic acid or hydrochloric acid and the like. Inaddition, compounds such as (XIX) can be treated with an alkylatingagent of type (XI). For example, treatment with an alkyl chloride,bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs,or the like) in solvent such as DMF, DMA, THF or ethanol in the presenceof a base like NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ will give compounds offormula (II).

Referring to Scheme 4, compounds of formula (III) can be prepared asoutlined. The amine moiety in compounds of formula (XII) can be suitablyprotected, shown by substituent G, as an alkyl or benzyl amine, amide,carbamate or other groups such as those described in “Protecting GroupsIn Organic Synthesis”, 3^(rd) ed.; T. W. Greene and P. G. M. Wuts, JohnWiley & Sons, 1999. The condensation of an alkyl or aryl hydrazine oftype (XXVIII), or the salt thereof, with compounds of formula (XII) in asolvent like methanol, ethanol, isopropanol or t-butyl alcohol attemperatures from 20 to 80° C. with or without a base such as NaHCO₃,Na₂CO₃, K₂CO₃, Cs₂CO₃, triethylamine or diisopropylethylamine willafford compounds of formula (XXIX). Preferred solvents are ethanol andt-butyl alcohol with preferred bases being triethylamine anddiisopropylethylamine. Compounds of formula (XXIX) can be converted intoa precursor for transition metal-catalyzed cross-coupling reactions,such as Stille, Suzuki, Negishi or other such coupling reactions knownto one skilled in the art. For example, treatment with POCl₃, PCl₃,PCl₅, PBr₃ or POBr₃ can afford the corresponding 3-halopyrazoles. Apreferred method would involve treatment with a triflating agent such astrifluoromethanesulfonic anhydride orN-phenyltrifluoromethanesulfonimide in DCE, CH₂Cl₂, THF or the like inthe presence of a base like pyridine, triethylamine ordiisopropylethylamine to provide pyrazole triflates of formula (XXX).Treatment of triflates of formula (XXX) with an organoboron compound offormula (XVII) in the presence of a catalyst like Pd(PPh₃)₄,PdCl₂(PPh₃)₂, PdCl₂(Po-tol₃)₂, PdCl₂(dppe) or PdCl₂(dppf) in a solventsuch as THF, 1,4-dioxane, DMA, DMF, DME, toluene, toluene/ethanol, ortoluene/H₂O mixtures, in the presence of a base such as Na₂CO₃, K₂CO₃,Cs₂CO₃, K₃PO₄, KF, CsF, KOAc or the like will afford compounds offormula (XXVI). Preferred catalysts are Pd(PPh₃)₄ and PdCl₂(dppf), withor without additives such as dppf and catalytic Bu₄NBr. Preferredsolvents are THF, 1,4-dioxane, toluene, and toluene/H₂O mixtures withpreferred bases being Na₂CO₃, K₂CO₃, Cs₂CO₃, and K₃PO₄. The protectinggroup on the nitrogen of compounds of formula (XXVI) may be removedusing generally accepted methods, which one skilled in the art wouldrecognize. More specifically, a group such as a t-butyl carbamate can beremoved with an acid like trifluoroacetic acid or hydrochloric acid andthe like in a solvent such as CH₂Cl₂, ethanol or methanol to affordcompounds of formula (XXVII). Compounds of formula (XXVII) or (III) maybe converted to their corresponding salts using methods known to thoseskilled in the art. It will be generally recognized that compounds offormula (XXVII) represent a subset of compounds of formula (III) whereinR¹ is equal to H.

Compounds such as (III) can be prepared from compounds of type (XXVII)using conventional synthetic methods such as alkylation or reductiveamination. Thus, treatment of compounds of formula (XXVII) with acompound of formula (X) containing a carbonyl group in the presence of areductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in thepresence of a catalyst in a solvent such as CH₂Cl₂, DCE, THF, ethanol,methanol or similar will afford compounds of formula (III). One skilledin the art will recognize that the addition of acid to decrease the pHof the reaction mixture to less than pH 7 may be required. Examples ofacids may include AcOH, Ti(O-iPr)₄, trifluoroacetic acid or hydrochloricacid and the like. In addition, compounds such as (XXVII) can be treatedwith an alkylating agent of type (XI). For example, treatment with analkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl,Br, I, OMs, OTs, or the like) in solvent such as DMF, DMA, THF orethanol in the presence of a base like NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃will afford compounds of formula (III).

Referring to Scheme 5, in an alternative embodiment, compounds offormula (II) may be prepared from a ketone of formula (XXXI). A ketoneof formula (XXXI) may be converted to the pyrazole of formula (XXXII)according to the procedure shown in Scheme 3 for the conversion of acompound of formula (XX) to a compound of formula (XVIII). A compound offormula (XXXIII) may be prepared from a compound of formula (XXXII) upontreatment with aqueous acid. For example, treatment of a compound offormula (XXXII) with HCl in aqueous THF at elevated temperatures willafford compounds of formula (XXXIII). A ketone of formula (XXXIII) maybe converted to an oxime of formula (XXXIV) by treatment withhydroxylamine, preferably upon treatment with hydroxylamine in pyridine.Compounds of formula (XXXIV) may exist as a single isomer or mixture ofstereoisomers. Treatment of an oxime of formula (XXXIV) with a hydridereducing agent can afford compounds of formula (XIX). In a preferredembodiment, the reducing agent is diisobutylaluminum hydride in CH₂Cl₂.Conversion of compounds of formula (XIX) to compounds of formula (II)can be effected using the methods described in Scheme 3.

Referring to Scheme 6, in an alternative embodiment, compounds offormula (XIX) may also be prepared as outlined. The amine moiety incompounds of formula (XIII) can be suitably protected, shown bysubstituent G, as an alkyl or benzyl amine, amide, carbamate or othergroups such as those described in “Protecting Groups In OrganicSynthesis”, 3^(rd) ed.; T. W. Greene and P. G. M. Wuts, John Wiley &Sons, 1999. Preferably, the sequence outlined in Scheme 6 may beemployed for compounds where p=1, m=2, and G=t-butyl carbamoyl.Treatment of pyrazolones of formula (XIII) with a triflating agent suchas N-phenyltrifluoromethanesulfonimide or trifluoromethanesulfonicanhydride in pyridine or another non-nucleophilic amine base givespyrazole triflates of formula (XXXV). Compounds such as (XXXV) can betreated with an alkylating agent of formula (XIV). For example,treatment with an alkyl or benzyl chloride, bromide, iodide, mesylate ortosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in DMF, DMA, THFor ethanol in the presence of a base like NaHCO₃, Na₂CO₃, NaH, K₂CO₃,Cs₂CO₃, or potassium tert-butoxide will afford compounds of formula(XVI). Preferably, alkylation is affected using alkylating agents suchas benzyl bromide in the presence of a suitable base such as potassiumtert-butoxide. Pyrazoles of formula (XVI) can be carried forward asdescribed in Scheme 2 to provide compounds of formula (XIX) and (II).

The compounds of the present invention are serotonin receptormodulators, and as such, the compounds are useful in the treatment ofserotonin-mediated disease states. Particularly, the compounds may beused in the treatment or prevention of CNS disorders, such as sleepdisorders, depression/anxiety, generalized anxiety disorder,schizophrenia, bipolar disorders, psychotic disorders,obsessive-compulsive disorder, mood disorders, post-traumatic stress andother stress-related disorders, migraine, pain, eating disorders,obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance,alcohol abuse, addictive disorders, nausea, inflammation, centrallymediated hypertension, sleep/wake disturbances, jetlag, and circadianrhythm abnormalities. The compounds may also be used in the treatmentand prevention of hypotension, peripheral vascular disorders,cardiovascular shock, renal disorders, gastric motility, diarrhea,spastic colon, irritable bowel disorders, ischemias, septic shock,urinary incontinence, and other disorders related to thegastrointestinal and vascular systems. In addition, compounds of thepresent invention may be used in the treatment or prevention of a rangeof ocular disorders including glaucoma, optic neuritis, diabeticretinopathy, retinal edema, and age-related macular degeneration.

The compounds of the present invention are 5-HT₇ modulators and many are5-HT₇ antagonists. As such, the compounds are useful in the treatment of5-HT₇-mediated disease states. Where the compounds possess substantial5-HT₇ antagonist activity, they may be particularly useful in thetreatment or prevention of depression/anxiety, sleep/wake disturbances,jetlag, migraine, urinary incontinence, gastric motility, and irritablebowel disorders. Many of the compounds of the present invention are5-HT₂ modulators and many are 5-HT₂ antagonists. As such, the compoundsare useful in the treatment of 5-HT₂-mediated diseases and conditions.Where the compounds possess substantial 5-HT₂ antagonist activity, theymay be particularly useful in the treatment or prevention ofdepression/anxiety, generalized anxiety disorder, schizophrenia, bipolardisorders, psychotic disorders, obsessive-compulsive disorder, mooddisorders, post-traumatic stress disorders, sleep disturbances, sexualdysfunction, eating disorders, migraine, addictive disorders, andperipheral vascular disorders.

It is anticipated that the compounds of the invention can beadministered by oral or parenteral routes, including intravenous,intramuscular, intraperitoneal, subcutaneous, rectal and topicaladministration, and inhalation. For oral administration, the compoundsof the invention will generally be provided in the form of tablets orcapsules or as an aqueous solution or suspension. Tablets for oral usemay include the active ingredient mixed with pharmaceutically acceptableexcipients such as inert diluents, disintegrating agents, bindingagents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate and lactose.Cornstarch and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract. Capsules for oral use include hard gelatincapsules in which the active ingredient is mixed with a solid diluentand soft gelatin capsules wherein the active ingredient is mixed withwater or an oil such as peanut oil, liquid paraffin or olive oil. Forintramuscular, intraperitoneal, subcutaneous and intravenous use, thecompounds of the invention will generally be provided in sterile aqueoussolutions or suspensions, buffered to an appropriate pH and isotonicity.Suitable aqueous vehicles include Ringer's solution and isotonic sodiumchloride. Aqueous suspensions according to the invention may includesuspending agents such as cellulose derivatives, sodium alginate,polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such aslecithin. Suitable preservatives for aqueous suspensions include ethyland n-propyl p-hydroxybenzoate.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition being treated, the route of administration andthe weight of the patient. In general, however, it is anticipated thatthe daily dose (whether administered as a single dose or as divideddoses) will be in the range 0.01 to 1000 mg per day, more usually from 1to 500 mg per day, and most usually from 10 to 200 mg per day. Expressedas dosage per unit body weight, a typical dose will be expected to bebetween 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

Examples

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Protocol for Preparative Reversed-Phase HPLC Gilson®

-   Column: YMC-Pack ODS-A, 5 μm, 75×30 mm-   Flow rate: 25 mL/min-   Detection: λ=220 & 254 nm-   Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1)  0.0 min 15% acetonitrile/85% water 2) 20.0 min 99% acetonitrile/1%water

Protocol for HPLC (Reversed-Phase) Method A: Hewlett Packard Series 1100

-   Column: Agilent ZORBAX® Bonus RP, 5 μm, 4.6×250 mm-   Flow rate: 1 mL/min-   Detection: λ=220 & 254 nm-   Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1)  0.0 min  1% acetonitrile/99% water 2) 20.0 min 99% acetonitrile/1%water

Method B: Hewlett Packard HPLC

-   Column: Agilent ZORBAX® Eclipse XDB-C8, 5 μm, 4.6×150 mm-   Flow rate: 1 mL/min-   Detection: λ=220 & 254 nm-   Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1) 0.0 min  1% acetonitrile/99% water 2) 8.0 min 99% acetonitrile/1%water 3) 12.0 min  99% acetonitrile/1% water

Protocol for Preparative SFC Thar Technologies®

-   Column: Chiracel AD, 10 μm, 250×20 mm-   Flow rate: 37 gm/min-   Detection: λ=220 & 254 nm-   Mobile phase: Isocratic 30% IPA/70% CO₂-   Pressure: 150 Bar-   Temperature: 35° C.

Protocol for Analytical SFC Jasco®

-   Column: Chiracel AD, 10 μm, 250×4.6 mm-   Flow rate: 1 gm/min-   Detection: λ=220 & 254 nm-   Mobile phase: Isocratic 30% IPA/70% CO₂-   Pressure: 150 Bar-   Temperature: 35° C.

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz),DPX500 (500 MHz), or DPX600 (600 MHz) spectrometer. The format of the ¹HNMR data below is: chemical shift in ppm down field of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Example 1

1-Benzyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

Step A.1-Benzyl-3-(4-nitro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylicacid tert-butyl ester. To a stirred solution of4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.69 g) in toluene(5 mL) was added 378 μL of benzylamine. The mixture was stirred for 10min and then 0.70 g of silica gel (SiO₂) was added. After stirring at RTfor 8 h, 0.77 g of 1-nitro-4-(2-nitro-vinyl)-benzene in toluene (5 mL)was added and the mixture was stirred for 14 h at RT. The mixture wasthen filtered through diatomaceous earth and the filtrate wasconcentrated in vacuo. Chromatography on SiO₂ (8 to 20% EtOAc/hexanes)afforded 0.48 g of the desired compound. MS (ESI): exact mass calculatedfor C₂₅H₂₇N₃O₄, 433.20; found, m/z 434.2 [M+H]⁺, 456.2 [M+Na]⁺.

Step B. To a stirred solution of 0.20 g of the above compound in a 10:1mixture of CH₂Cl₂/MeOH (6 mL) was added 1.9 mL of 1.0 M HCl in Et₂O.After stirring for 12 h at RT, a white solid had formed, which wascollected by filtration to afford 0.11 g of the title compound. MS(ESI): exact mass calculated for C₂₀H₁₉N₃O₂, 333.15; found, m/z 334.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.26-8.21 (m, 2H), 7.59-7.55 (m, 2H),7.42 (s, 1H), 7.36 (t, J=7.4 Hz, 2H), 7.30 (t, J=7.4 Hz, 1 Hz), 7.20 (d,J=7.4 Hz, 2H), 5.19 (s, 2H), 4.44 (s, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.89(t, J=6.3 Hz, 2H).

Examples 2-25 were prepared according to the procedure described inExample 1, with alterations as noted.

Example 2

1-Benzyl-3-(3-chloro-4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.18 g) was prepared from 0.54 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 293 μL ofbenzylamine, and 0.62 g of 2-chloro-1-fluoro-4-(2-nitro-vinyl)-benzene.MS (ESI): exact mass calculated for C₂₀H₁₈ClFN₂, 340.11; found, m/z341.1 [M+H]⁺, 343.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.45-7.43 (m, 1H),7.36-7.16 (m, 8H), 5.15 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H),2.85 (t, J=6.3 Hz, 2H).

Example 3

4-(1-Benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-phenol

The title compound (0.09 g) was prepared from 1.22 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 856 μL ofbenzylamine, and 1.29 g of 4-(2-nitro-vinyl)-phenol, which was added inEtOH (12 mL). MS (ESI): exact mass calculated for C₂₀H₂₀N₂O, 304.16;found, m/z 305.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.35-7.32 (m, 2H),7.29-7.25 (m, 2H), 7.17-7.14 (m, 4H), 6.98 (s, 1H), 6.80-6.77 (m, 2H),5.12 (s, 2H), 4.31 (s, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz,2H).

Example 4

1-Benzyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.28 g) was prepared from 0.50 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 274 μL ofbenzylamine, and 0.59 g of 1-trifluoromethoxy-4-(2-nitro-vinyl)-benzeneusing CH₂Cl₂ as the solvent. MS (ESI): exact mass calculated forC₂₁H₁₉F₃N₂O, 372.14; found, m/z 373.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):7.44-7.41 (m, 2H), 7.37-7.26 (m, 5H), 7.19-7.17 (m, 3H), 5.15 (s, 2H),4.37 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).

Example 5

1-Benzyl-3-(5-chloro-thiophen-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (82.3 mg) was prepared from 0.56 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL ofbenzylamine, and 0.53 g of 2-chloro-5-(2-nitro-vinyl)-thiophene. MS(ESI): exact mass calculated for C₁₈H₁₇ClN₂S, 328.08; found, m/z 329.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.36-7.33 (m, 2H), 7.30-7.27 (m, 1H),7.17-7.15 (m, 2H), 7.12 (s, 1H), 6.89 (d, J=3.8 Hz, 1H), 6.73 (d, J=3.8Hz, 1H), 5.12 (s, 2H), 4.31 (s, 2H), 3.48 (t, J=6.3 Hz, 2H), 2.84 (t,J=6.3 Hz, 2H).

Example 6

1-Benzyl-3-thiophen-2-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (136.8 mg) was prepared from 0.53 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL ofbenzylamine, and 0.41 g of 2-(2-nitro-vinyl)-thiophene. MS (ESI): exactmass calculated for C₁₈H₁₈N₂S, 294.12; found, m/z 295.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.36-7.32 (m, 2H), 7.30-7.26 (m, 1H), 7.22 (dd, J=5.2,1.1 Hz, 1H), 7.18-7.15 (m, 2H), 7.12 (s, 1H), 7.02 (dd, J=5.2, 3.6 Hz,1H), 6.94 (dd, J=3.6, 1.1 Hz, 1H), 5.13 (s, 2H), 4.34 (s, 2H), 3.49 (t,J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).

Example 7

1-(3-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (159.0 mg) was prepared from 0.55 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of3-chlorobenzylamine, and 0.40 g of (2-nitro-vinyl)-benzene and withoutSiO₂. MS (ESI): exact mass calculated for C₂₀H₁₉ClN₂, 322.12; found, m/z323.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.38-7.32 (m, 5H), 7.31-7.28 (m,1H), 7.23-7.19 (m, 1H), 7.17-7.16 (m, 1H), 7.13 (s, 1H), 7.12-7.10 (m,1H), 5.16 (s, 2H), 4.37 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3Hz, 2H).

Example 8

1-Benzyl-3-(3-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (282.6 mg) was prepared from 0.61 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 330 μL ofbenzylamine, and 0.50 g of (2-nitro-vinyl)-3-fluorobenzene, using EtOHas the solvent and without SiO₂. MS (ESI): exact mass calculated forC₂₀H₁₉FN₂, 306.15; found, m/z 307.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.38-7.32 (m, 3H), 7.30-7.26 (m, 1H), 7.20-7.14 (m, 4H), 7.10-7.06 (m,1H), 6.95-6.90 (m, 1H), 5.15 (s, 2H), 4.36 (s, 2H), 3.50 (t, J=6.3 Hz,2H), 2.86 (t, J=6.3 Hz, 2H).

Example 9

3-(4-Chloro-phenyl)-1-(2-fluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (129.2 mg) was prepared from 0.49 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 286 μL of2-fluorobenzylamine, and 0.46 g of (2-nitro-vinyl)-4-chlorobenzene,replacing SiO₂ with crushed 4 Å molecular sieves. MS (ESI): exact masscalculated for C₂₀H₁₈ClFN₂, 340.11; found, m/z 341.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.38-7.30 (m, 5H), 7.18-7.12 (m, 3H), 7.10-7.06 (m, 1H),5.20 (s, 2H), 4.35-4.34 (m, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.94 (t, J=6.3Hz, 2H).

Example 10

1-(3-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (212.8 mg) was prepared from 0.55 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 340 ηL of3-chlorobenzylamine, and 0.51 g of (2-nitro-vinyl)-4-chlorobenzene,replacing SiO₂ with crushed 4 Å molecular sieves. MS (ESI): exact masscalculated for C₂₀H₁₈Cl₂N₂, 356.08; found, m/z 357.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.38-7.28 (m, 6H), 7.18-7.15 (m, 2H), 7.12-7.09 (m, 1H),5.16 (s, 2H), 4.36 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz,2H).

Example 11

1-(2-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (113.8 mg) was prepared from 0.55 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of2-chlorobenzylamine, 0.40 g of (2-nitro-vinyl)-benzene, and withoutSiO₂. MS (ESI): exact mass calculated for C₂₀H₁₉ClN₂, 322.12; found, m/z323.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.46 (m, 1H), 7.37-7.26 (m, 6H),7.22-7.19 (m, 1H), 7.07 (s, 1H), 6.85-6.82 (m, 1H), 5.25 (s, 2H), 4.39(s, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).

Example 12

1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (260.2 mg) was prepared from 0.55 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 340 μL of4-chlorobenzylamine, and 0.51 g of (2-nitro-vinyl)-4-chlorobenzene. MS(ESI): exact mass calculated for C₂₀H₁₈Cl₂N₂, 356.08; found, m/z 357.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.37-7.31 (m, 6H), 7.17-7.13 (m, 3H),5.15 (s, 2H), 4.35 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz,2H).

Example 13

1-Benzyl-3-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (454.6 mg) was prepared from 0.52 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 280 μL ofbenzylamine, and 0.57 g of 2,4-dichloro-1-(2-nitro-vinyl)-benzene, usinga 5:1 EtOH/toluene mixture as the solvent. MS (ESI): exact masscalculated for C₂₀H₁₈Cl₂N₂, 356.08; found, m/z 357.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.53 (d, J=2.2 Hz, 1H), 7.36-7.32 (m, 3H), 7.30-7.28 (m,2H), 7.20-7.17 (m, 2H), 7.04 (s, 1H), 5.16 (s, 2H), 4.13 (s, 2H), 3.50(t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).

Example 14

1-(4-Methoxy-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.19 g) was prepared from 1.51 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 1.0 mL of4-methoxybenzylamine, and 1.13 g of (2-nitro-vinyl)-benzene, using EtOHas the solvent and omitting SiO₂. MS (ESI): exact mass calculated forC₂₁H₂₂N₂O, 318.17; found, m/z 319.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.39-7.30 (m, 4H), 7.20-7.15 (m, 1H), 7.14-7.11 (m, 2H), 7.08 (s, 1H),6.90-6.87 (m, 2H), 5.05 (s, 2H), 4.34 (s, 2H), 3.50 (t, J=6.3 Hz, 2H),2.88 (t, J=6.3 Hz, 2H).

Example 15

1-(2-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (149.9 mg) was prepared from 0.50 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 304 μL of2-chlorobenzylamine, and 0.46 g of (2-nitro-vinyl)-4-chlorobenzene,replacing SiO₂ with crushed 4 Å molecular sieves. MS (ESI): exact masscalculated for C₂₀H₁₈Cl₂N₂, 356.08; found, m/z 357.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.58-7.56 (m, 1H), 7.47-7.45 (m, 1H), 7.37-7.26 (m, 5H),7.10 (s, 1H), 6.85-6.82 (m, 1H), 5.25 (s, 2H), 4.38 (s, 2H), 3.53 (t,J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).

Example 16

1-(2,4-Dichloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.43 g) was prepared from 0.55 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 370 μL of2,4-dichlorobenzylamine, and 0.41 g of (2-nitro-vinyl)-benzene, usingEtOH as the solvent. MS (ESI): exact mass calculated for C₂₀H₁₈Cl₂N₂,356.08; found, m/z 357.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.55-7.50 (m,2H), 7.37-7.29 (m, 4H), 7.22-7.18 (m, 1H), 7.07 (s, 1H), 6.77 (d, J=8.5Hz, 1H), 5.23 (s, 2H), 4.38 (s, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.86 (t,J=6.3 Hz, 2H).

Example 17

1-Benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (89.4 mg) was prepared from 0.51 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 272 μL ofbenzylamine, and 0.41 g of (2-nitro-propenyl)-benzene. MS (ESI): exactmass calculated for C₂₁H₂₂N₂, 302.18; found, m/z 303.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 7.41-7.36 (m, 2H), 7.35-7.30 (m, 2H), 7.28-7.21 (m,4H), 7.05-7.01 (m, 2H), 5.16 (s, 2H), 4.18 (s, 2H), 3.52 (t, J=6.3 Hz,2H), 2.89 (t, J=6.3 Hz, 2H).

Example 18

1-Benzyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (89.7 mg) was prepared from 0.51 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 272 μL ofbenzylamine, and 0.41 g of 1-methyl-4-(2-nitro-vinyl)-benzene. MS (ESI):exact mass calculated for C₂₁H₂₂N₂, 302.18; found, m/z 303.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD): 7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.23-7.20(m, 2H), 7.18-7.14 (m, 4H), 7.06 (s, 1H), 5.13 (s, 2H), 4.33 (s, 2H),3.49 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).

Example 19

1-Benzyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (228.2 mg) was prepared from 0.49 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 268 μL ofbenzylamine, and 0.55 g of 1,2-dichloro-4-(2-nitro-vinyl)-benzene. MS(ESI): exact mass calculated for C₂₀H₁₈Cl₂N₂, 356.08; found, m/z 357.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.51-7.47 (m, 2H), 7.36-7.32 (m, 2H),7.32-7.25 (m, 2H), 7.22 (s, 1H), 7.19-7.15 (m, 2H), 5.15 (s, 2H), 4.35(s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).

Example 20

3-Benzo[1,3]dioxol-5-yl-1-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (306.0 mg) was prepared from 0.49 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 268 μL ofbenzylamine, and 0.48 g of 5-(2-nitro-vinyl)-benzo[1,3]dioxole. MS(ESI): exact mass calculated for C₂₁H₂₀N₂O₂, 332.15; found, m/z 333.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.36-7.30 (m, 2H), 7.29-7.24 (m, 1H),7.18-7.14 (m, 2H), 7.01 (s, 1H), 6.85-6.75 (m, 3H), 5.93 (s, 2H), 5.12(s, 2H), 4.31 (s, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).

Example 21

1-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (706.2 mg) was prepared from 1.31 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 700 μL ofbenzylamine, and 1.10 g of 1-fluoro-4-(2-nitro-vinyl)-benzene. MS (ESI):exact mass calculated for C₂₀H₁₉FN₂, 306.15; found, m/z 307.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD): 7.36-7.25 (m, 5H), 7.18-7.15 (m, 2H), 7.11-7.05(m, 3H), 5.13 (s, 2H), 4.33 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.86 (t,J=6.3 Hz, 2H).

Example 22

1-Butyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (292.8 mg) was prepared from 0.56 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 μL ofbutylamine, and 0.45 g of 1-methyl-4-(2-nitro-vinyl)-benzene. MS (ESI):exact mass calculated for C₁₈H₂₄N₂, 268.19; found, m/z 269.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD): 7.20-7.14 (m, 4H), 6.93 (s, 1H), 4.32 (s, 2H),3.88 (t, J=7.1 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H),2.32 (s, 3H), 1.77-1.70 (m, 2H), 1.41-1.33 (m, 2H), 0.97 (t, J=7.4 Hz,3H).

Example 23

1-Benzyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.38 g) was prepared from 0.66 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL ofbenzylamine, and 0.63 g of 1-bromo-4-(2-nitro-vinyl)-benzene. MS (ESI):exact mass calculated for C₂₀H₁₉BrN₂, 366.07; found, m/z 367.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.51-7.48 (m, 2H), 7.36-7.32 (m, 2H), 7.30-7.25(m, 3H), 7.19-7.16 (m, 2H), 5.14 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).

Example 24

1-Benzyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.23 g) was prepared from 0.50 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 274 μL ofbenzylamine, and 0.55 g of 1-trifluoromethyl-4-(2-nitro-vinyl)-benzene,using acetonitrile as the solvent. MS (ESI): exact mass calculated forC₂₁H₁₉F₃N₂, 356.16; m/z found, 357.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.65-7.63 (m, 2H), 7.54-7.52 (m, 2H), 7.36-7.27 (m, 4H), 7.20-7.18 (m,2H), 5.17 (s, 2H), 4.40 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3Hz, 2H).

Example 25

1-Benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (1.19 g) was prepared from 1.55 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 850 μL ofbenzylamine, and 1.43 g of 1-chloro-4-(2-nitro-vinyl)-benzene, using a1:1 mixture of EtOH/toluene as the solvent. MS (ESI): exact masscalculated for C₂₀H₂₀Cl₂N₂, 322.12; m/z found, 323.2 [M+H]⁺, 325.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.37-7.26 (m, 7H), 7.18-7.16 (m, 3H),5.15 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz,2H).

Example 26

1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine

Step A.1-Benzyl-3-phenyl-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylicacid tert-butyl ester. A solution of the compound (0.53 g) from Example59, Step B, and 272 μL of benzylamine in benzene (10 mL) was heated atreflux for 24 h using a Dean-Stark apparatus. The solvent was removed,the crude material was dissolved in toluene (10 mL), and 0.38 g of(2-nitro-vinyl)-benzene was added. The mixture was stirred for 24 h atRT and concentrated in vacuo. Chromatography on SiO₂ (1 to 20%EtOAc/hexanes) afforded 108.0 mg of the desired compound. MS (ESI):exact mass calculated for C₂₆H₃₀N₂O₂, 402.53; found, m/z 403.2 [M+H]⁺.

Step B. To a stirred solution of the compound from Step A (108.0 mg) inCH₂Cl₂ (5 mL) was added TFA (1 mL). The mixture was stirred at RT for 12h and then concentrated in vacuo. The residue was partitioned betweenCH₂Cl₂ (10 mL) and 1 M NaOH (10 mL). The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2×10 mL). The combined organiclayers were concentrated. Chromatography on SiO₂ (5% 2 M NH₃ inMeOH/CH₂Cl₂) gave 66.5 mg of the title compound. MS (ESI): exact masscalculated for C₂₁H₂₂N₂, 302.41; found, m/z 303.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.42-7.22 (m, 8H), 7.08 (m, 2H), 6.67 (s, 1H), 5.08 (s,2H), 3.06-2.91 (m, 4H), 2.90-2.82 (m, 2H), 2.77-2.68 (m, 2H), 2.25 (brs, 1H).

Example 27

1-Benzyl-3-(5-methyl-thiophen-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

Step A.1-Benzyl-3-(5-methyl-thiophen-2-yl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylicacid tert-butyl ester. A mixture of 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (0.54 g) and 300 μL of benzylamine in toluene (10 mL)was heated at reflux for 6 h using a Dean-Stark apparatus. The solutionwas cooled to RT and 0.47 g of 2-methyl-5-(2-nitro-vinyl)-thiophene wasadded. The mixture was stirred for 16 h at RT and then was concentratedin vacuo. The residue was chromatographed on SiO₂ (1 to 30%EtOAc/hexanes) to afford 281.9 mg of the desired compound. TLC (SiO₂,33% EtOAc/hexanes): R_(f)=0.54.

Step B. To a stirred solution of the compound from Step A (281.9 mg) inEtOH (10 mL) was added HCl (1 M in Et₂O, 5 mL). The resulting mixturewas stirred at RT for 24 h and concentrated in vacuo. The residue wasthen partitioned between CH₂Cl₂ (10 mL) and 1 M NaOH (10 mL). The layerswere separated and the aqueous layer was extracted with CH₂Cl₂ (2×10mL). The combined organic layers were concentrated. Chromatography onSiO₂ (CH₂Cl₂ to 5% 2 M NH₃ in MeOH/CH₂Cl₂) gave 59.0 mg of the titlecompound. MS (ESI): exact mass calculated for C₁₉H₂₀N₂S, 308.13; found,m/z 309.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.35-7.25 (m, 3H), 7.09-7.06(m, 2H), 6.76 (s, 1H), 6.65-6.62 (m, 2H), 4.96 (s, 2H), 4.03 (s, 2H),3.14 (t, J=5.8 Hz, 2H), 2.50 (t, J=5.8 Hz, 2H), 2.45 (s, 3H).

Example 28

1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine

Step A.1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylicacid tert-butyl ester. The desired compound (54.2 mg) was prepared fromthe compound of Example 59, Step B (0.56 g), 280 μL of benzylamine, and0.49 g of 1-chloro-4-(2-nitro-vinyl)-benzene as in Example 1, Step A. MS(ESI): exact mass calculated for C₂₆H₂₉ClN₂O₂, 436.19; found, m/z 437.2[M+H]⁺.

Step B. The above compound (54.2 mg) was converted to the title compound(19.2 mg) as in Example 27, Step B. MS (ESI): exact mass calculated forC₂₁H₂₁ClN₂, 336.14; found, m/z 337.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.34-7.24 (m, 7H), 7.04 (d, J=7.1 Hz, 2H), 6.62 (s, 1H), 5.05 (s, 2H),3.03-3.00 (m, 2H), 2.97-2.94 (m, 2H), 2.83-2.80 (m, 2H), 2.74-2.71 (m,2H).

Example 29

1-Benzyl-3-(5-chloro-thiophen-2-yl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine

Step A.1-Benzyl-3-(5-chloro-thiophen-2-yl)-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylicacid tert-butyl ester. The desired compound (124.5 mg) was prepared fromthe compound of Example 59, Step B (0.55 g), 280 μL of benzylamine, and0.49 g of 2-chloro-5-(2-nitro-vinyl)-thiophene as in Example 1, Step A.MS (ESI): exact mass calculated for C₂₄H₂₇ClN₂O₂S, 442.15; found, m/z443.2 [M+H]⁺.

Step B. The above compound (124.5 mg) was converted to the titlecompound (30.7 mg) as in Example 27, Step B. MS (ESI): exact masscalculated for C₁₉H₁₉ClN₂S, 342.10; found, m/z 343.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.04-7.00 (m, 2H),6.82 (d, J=3.8 Hz, 1H), 6.66 (s, 1H), 6.64 (d, J=3.8 Hz, 1H), 5.02 (s,2H), 3.06-3.03 (m, 2H), 2.97-2.93 (m, 2H), 2.88-2.84 (m, 2H), 2.72-2.68(m, 2H).

Example 30

1-(4-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

Step A.1-(4-Chloro-benzyl)-3-phenyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylicacid tert-butyl ester. The desired compound (405.6 mg) was prepared from0.53 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of2-chlorobenzylamine, and 0.34 g of (2-nitro-vinyl)-benzene as in Example1, Step A. MS (ESI): exact mass calculated for C₂₅H₂₇ClN₂O₂, 422.18;found, m/z 423.2 [M+H]⁺.

Step B. The above compound (405.6 mg) was converted to the titlecompound (206.7 mg) as in Example 27, Step B, using MeOH as the solvent.The desired product was then treated with malic acid (75.0 mg) in EtOAc.The solids were collected by filtration to give the correspondingmaleate salt. MS (ESI): exact mass calculated for C₂₀H₁₉ClN₂, 322.12;found, m/z 323.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.37-7.32 (m, 6H),7.22-7.18 (m, 1H), 7.16-7.13 (m, 2H), 7.12 (s, 1H), 6.24 (s, 2H), 5.14(s, 2H), 4.35 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.84 (t, J=6.3 Hz, 2H).

Example 31

1-Benzyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

Step A.1-Benzyl-3-phenyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylicacid tert-butyl ester. The desired compound (380.7 mg) was prepared from0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 280 μL ofbenzylamine, and 0.39 g of (2-nitro-vinyl)-benzene as in Example 1, StepA. MS (ESI): exact mass calculated for C₂₅H₂₈N₂O₂, 388.22; found, m/z389.2 [M+H]⁺.

Step B. The above compound (0.37 g) was converted to the title compound(234.7 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₂₀H₂₀N₂, 288.16; found, m/z 289.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.27-7.23 (m, 6H), 7.22-7.17 (m, 1H), 7.12-7.07 (m, 1H), 7.03-6.99 (m,2H), 6.77 (s, 1H), 4.93 (s, 2H), 3.98 (s, 2H), 3.07 (t, J=5.8 Hz, 2H),2.48 (t, J=5.8 Hz, 2H).

Example 32

1-Benzyl-3-(3-chloro-phenyl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine

To a solution of the compound from Example 59, Step B (0.51 g) intoluene (5 mL) was added 280 μL of benzylamine and 0.8 mL of Ti(OiPr)₄.The resulting mixture was stirred for 3 h at RT.1-Chloro-3-(2-nitro-vinyl)-benzene (0.46 g) was then added in oneportion and stirring was continued for an additional 16 h at RT. Themixture was poured into water and filtered through diatomaceous earth.The aqueous filtrate was extracted with EtOAc (3×20 mL) and the combinedorganic layers were concentrated in vacuo. Chromatography on SiO₂ (1 to35% EtOAc/hexanes) afforded 106.7 mg of1-benzyl-3-(3-chloro-phenyl)-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylicacid tert-butyl ester. This compound was then converted to the titlecompound (19.1 mg) as in Example 27, Step B, using 10:1 CH₂Cl₂/MeOH asthe solvent. MS (ESI): exact mass calculated for C₂₁H₂₁ClN₂, 336.14;found, m/z 337.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.36-7.30 (m, 3H),7.29-7.25 (m, 2H), 7.23-7.17 (m, 2H), 7.05-7.02 (m, 2H), 6.64 (s, 1H),5.05 (s, 2H), 3.01-2.98 (m, 2H), 2.94-2.91 (m, 2H), 2.82-2.97 (m, 2H),2.71-2.68 (m, 2H).

Example 33

1-Benzyl-3-(3-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (193.3 mg) was prepared from 0.50 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 μL ofbenzylamine, and 0.45 g of 1-chloro-3-(2-nitro-vinyl)-benzene as inExample 9. MS (ESI): exact mass calculated for C₂₀H₁₉ClN₂, 322.12;found, m/z 323.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.36-7.20 (m, 6H),7.14-7.07 (m, 3H), 6.81 (s, 1H), 5.01 (s, 2H), 4.04 (s, 2H), 3.14 (t,J=5.8 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H).

Example 34

1-Benzyl-3-(4-methoxy-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

Step A.1-Benzyl-3-(4-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylicacid tert-butyl ester. To a solution of 0.50 g of4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 260 μL ofbenzylamine in toluene (5 mL) was added 0.48 g of MgSO₄ and 16.7 mg ofBu₂SnCl₂. After 1 h, 0.45 g of 1-methoxy-4-(2-nitro-vinyl)-benzene wasadded and the mixture was stirred for 16 h at RT. The mixture was thendiluted with water (80 mL) and extracted with EtOAc (3×15 mL) and thecombined organic layers were concentrated in vacuo. Chromatography onSiO₂ (1 to 20% EtOAc/hexanes) afforded 0.38 g of the desired compound.MS (ESI): exact mass calculated for C₂₆H₃₀N₂O₃, 418.23; found, m/z 419.2[M+H]⁺.

Step B. The above compound (0.47 g) was converted to the title compound(275.2 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₂₁H₂₂N₂O, 318.17; found, m/z 319.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.35-7.24 (m, 5H), 7.12-7.08 (m, 2H), 6.90-6.86 (m, 2H), 6.74 (s, 1H),4.99 (s, 2H), 4.04 (s, 2H), 3.81 (s, 3H), 3.16 (t, J=5.8 Hz, 2H), 2.53(t, J=5.8 Hz, 2H).

Example 35

1-Benzyl-3-(4-chloro-phenyl)-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

To a solution of1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(Example 25; 0.11 g) in 1,2-dichloroethane (5 mL) was added 18 μL ofacetic acid, 26 μL of acetaldehyde, and 0.10 g of NaBH(OAc)₃. Themixture was stirred at RT for 15 h. The mixture was diluted with CH₂Cl₂and washed with satd. aq. NaHCO₃ (2×). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatographyon SiO₂ (1% 2 M NH₃ in MeOH/CH₂Cl₂) afforded 0.02 g of the titlecompound. The product was dissolved in Et₂O and treated with excess 1.0M HCl in Et₂O to afford 0.02 g of the corresponding HCl salt. MS (ESI):exact mass calculated for C₂₂H₂₃ClN₂, 350.15; found, m/z 351.2 [M+H]⁺,353.2 [M+H]⁺. ¹H NMR 500 MHz, CD₃OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m,3H), 5.17-5.13 (m, 2H), 4.48-4.37 (m, 2H), 3.85-3.76 (m, 2H), 3.45-3.23(m, 2H), 3.00-2.84 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).

Example 36

1-Benzyl-3-(4-chloro-phenyl)-5-isopropyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.1 g) was prepared from1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(Example 25; 0.10 g) and 32 μL of acetone as in Example 35. MS (ESI):exact mass calculated for C₂₃H₂₅ClN₂, 364.17; found, m/z 365.2 [M+H]⁺,367.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.37-7.27 (m, 7H), 7.21-7.17 (m,3H), 5.15 (d, J=5.2 Hz, 2H), 4.58-4.54 (m, 1H), 4.28-4.25 (m, 1H),3.78-3.65 (m, 2H), 3.45-3.35 (m, 1H), 3.03-2.85 (m, 2H), 1.42 (t, J=6.6Hz, 6H).

Example 37

3-[1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl]-propan-1-ol

To a solution of1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(Example 25; 0.51 g) in DMF (14 mL) was added 1.39 g of Cs₂CO₃ and 142μL of 3-bromo-1-propanol. The mixture was stirred at RT for 12 h andthen was diluted with water. The aqueous layer was extracted with Et₂Oand the combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatography on SiO₂ (2% 2 M NH₃ inMeOH/CH₂Cl₂) afforded 0.15 g of the title compound. The product wasdissolved in Et₂O and treated with excess 1.0 M HCl in Et₂O to afford0.16 g the corresponding HCl salt. MS (ESI): exact mass calculated forC₂₃H₂₅ClN₂O, 380.17; found, m/z 381.2 [M+H]⁺, 383.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.15 (s, 2H), 4.47(br s, 2H), 3.93-3.25 (m, 6H), 2.94-2.93 (m, 2H), 2.01-1.96 (m, 2H).

Example 38

b1-Benzyl-3-(4-chloro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

Step A.1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylicacid ethyl ester. To a stirred solution of 3.0 g of4-oxo-piperidine-1-carboxylic acid ethyl ester in benzene (35 mL) wasadded 1.91 mL of benzylamine. The mixture was heated at reflux for 24 husing a Dean-Stark apparatus. The solvent was removed to give a paleyellow oil. A portion of the crude product (0.50 g) was dissolved intoluene (4 mL) and 0.35 g of 1-chloro-4-(2-nitro-vinyl)-benzene wasadded, followed by 0.7 g of 4 Å molecular sieves. The resulting mixturewas stirred for 12 h at RT. The mixture was then filtered throughdiatomaceous earth and the filtrate was washed with satd. aq. NH₄Cl(3×). The combined organic extracts were dried over Na₂SO₄, filtered,and concentrated in vacuo. Chromatography on SiO₂ (8% EtOAc/hexanes)afforded 0.25 g the title compound. TLC (SiO₂, 25% EtOAc/hexanes):R_(f)=0.34. MS (ESI): exact mass calculated for C₂₃H₂₃ClN₂O₂, 394.14;found, m/z 395.2 [M+H]⁺, 397.2 [M+H]⁺, 417.1 [M+Na]⁺.

Step B. To a stirred solution of the above compound (0.25 g) in toluene(20 mL) was added 571 μL of sodium bis(2-methoxyethoxy)aluminum hydride(Red-Al, 1.5 M in toluene). The mixture was stirred for 48 h at RT andthen was quenched by the addition of satd. aq. potassium sodiumtartrate. The organic layer was separated and dried over Na₂SO₄,filtered, and concentrated in vacuo to give 0.16 g of the titlecompound. TLC (SiO₂, 10% MeOH/EtOAc): R_(f)=0.14. MS (ESI): exact masscalculated for C₂₁H₂₁ClN₂, 336.14; found, m/z 337.2 [M+H]⁺, 339.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.31-7.24 (m, 7H), 7.07-7.06 (m, 2H),6.76 (s, 1H), 4.98 (s, 2H), 3.56 (s, 2H), 2.72 (t, J=6.3 Hz, 2H), 2.60(t, J=6.3 Hz, 2H).

Example 39

1-Benzyl-3-(3-chloro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.34 g) was prepared from 3.0 g of4-oxo-piperidine-1-carboxylic acid ethyl ester, 1.91 mL of benzylamine,and 1.2 g of 1-chloro-3-(2-nitro-vinyl)-benzene as in Example 38. TLC(SiO₂, 2% NH₃ in MeOH/EtOAc): R_(f)=0.25. MS (ESI): exact masscalculated for C₂₁H₂₁ClN₂, 336.14; found, m/z 337.2 [M+H]⁺, 339.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.36-7.32 (m, 4H), 7.30-7.25 (m, 2H),7.21-7.16 (m, 4H), 5.15 (s, 2H), 4.41 (s, 2H), 3.53 (t, J=6.3 Hz, 2H),2.98 (s, 3H), 2.91 (t, J=6.3 Hz, 2H), 2.82-2.70 (m, 4H).

Example 40

1-Benzyl-3-(3-chloro-4-fluoro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (0.03 g) was prepared from1-benzyl-3-(3-chloro-4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(Example 2) and paraformaldehyde as in Example 35. The product was thendissolved in 1/1 EtOAc/CH₂Cl₂ and treated with 0.03 g (0.15 mmol) ofcitric acid to afford 0.05 g of the corresponding citrate salt. MS(ESI): exact mass calculated for C₂₁H₂₀ClFN₂, 354.13; found, m/z 355.1[M+H]⁺, 357.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.44-7.22 (m, 1H), 7.34(t, J=7.7 Hz, 2H), 7.30-7.26 (m, 2H), 7.22 (t, J=9.1 Hz, 1H), 7.19-7.13(m, 3H), 5.14 (s, 2H), 4.36 (s, 2H), 3.50 (t, J=5.8 Hz, 2H), 2.96 (s,3H), 2.89 (t, J=5.8, 2H), 2.82-2.71 (m, 4H).

Example 41

1,5-Dibenzyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

To a stirred solution of 0.46 mL of 1-benzyl-piperidin-4-one in absoluteEtOH (5 mL) was added 0.27 mL of benzylamine. After 3 h, the solvent wasremoved in vacuo. The residue was diluted with absolute EtOH (5 mL) and0.37 g of (2-nitro-vinyl)-benzene was added in one portion. The mixturewas stirred at RT for 16 h, filtered through diatomaceous earth, and thefiltrate was concentrated. Chromatography on SiO₂ (1 to 20%EtOAc/hexanes) afforded 0.48 g of the title compound. MS (ESI): exactmass calculated for C₂₇H₂₆N₂, 378.21; found, m/z 379.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.40-7.22 (m, 12H), 7.18-7.10 (m, 3H), 6.80 (s, 1H),4.99 (s, 2H), 3.78 (br m, 2H), 3.75 (s, 2H), 2.79-2.74 (m, 2H),2.59-2.55 (m, 2H).

Example 42

1-Benzyl-5-isopropyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

The title compound (111.0 mg) was prepared from 372 μL of1-isopropyl-piperidin-4-one, 270 μL of benzylamine, and 0.38 g of(2-nitro-vinyl)-benzene as in Example 41. The product was diluted withEtOAc and malic acid (39.0 mg) was added. The solids that formed werecollected by filtration to give the title compound as a maleate salt. MS(ESI): exact mass calculated for C₂₃H₂₆N₂, 330.21; found, m/z 331.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.38-7.33 (m, 6H), 7.30-7.27 (m, 1H),7.23-7.19 (m, 3H), 7.14 (s, 1H), 6.25 (s, 2H), 5.15 (s, 2H), 3.74-3.66(m, 1H), 2.96-2.91 (br m, 2H), 1.41 (d, J=6.6 Hz, 6H).

Example 43

1-Benzyl-3-(4-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. 3-Oxo-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of 5-oxo-azepane-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester (Example 59, Step A; 8.29 g) in 80mL of EtOH was added 1.5 mL of hydrazine hydrate. The solution washeated at reflux for 2 days and then was cooled to RT. The solventvolume was reduced to ca. 20 mL and the resulting solution was stored at−15° C. for 16 h. Water was added and the solids were collected byfiltration, washed with water, and dried to give 4.99 g of the desiredcompound as a white crystalline solid. MS (ESI): exact mass calculatedfor C₁₂H₁₉N₃O₃, 253.14; found, m/z 254.1 [M+H]⁺.

Step B.1-Benzyl-3-oxo-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a stirred solution of 1.16 g the compound fromstep A in 15 mL of DMF was added 1.80 g of Cs₂CO₃. The suspension wasstirred at RT for 20 min. Benzyl bromide (0.6 mL) was added and themixture was stirred at RT for an additional 12 h. The mixture wasdiluted with water and extracted with Et₂O. The combined organic layerswere washed with water, brine, dried over Na₂SO₄, and concentrated toafford 1.77 g of a colorless semi-solid. Chromatography on SiO₂ (15 to50% EtOAc/hexanes) over 1 h gave 1.21 g of the desired compound as amixture of mono-benzylated isomers. TLC (SiO₂, 50% EtOAc/hexanes):R_(f)=0.34. MS (ESI): exact mass calculated for C₁₉H₂₅N₃O₃, 343.19;found, m/z 344.2 [M+H]⁺, 366.2 [M+Na]⁺.

Step C.1-Benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a stirred solution of the above mixture ofregioisomers (1.21 g) in 35 mL of CH₂Cl₂ was added 1.93 mL of i-Pr₂NEtand 1.58 g of N-phenyltrifluoromethane-sulfonimide. The mixture washeated at reflux for 12 h and then was cooled and concentrated in vacuo.Chromatography on SiO₂ (5 to 20% EtOAc/hexanes) afforded 0.63 g of thedesired compound. TLC (SiO₂, 25% EtOAc/hexanes): R_(f)=0.37. MS (ESI):exact mass calculated for C₂₀H₂₄F₃N₃O₅S, 475.14; found, m/z 476.2[M+H]⁺. Also, 0.68 g of the undesired mono-benzylated3-benzyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acidtert-butyl ester was obtained.

Step D.1-Benzyl-3-(4-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of the compound from step C (0.17g) in 5 mL of THF was added 0.12 g of K₃PO₄, 0.08 g of4-trifluoromethylphenylboronic acid and 0.03 g of PdCl₂dppf. The mixturewas heated at reflux for 12 h. The mixture was cooled, filtered throughdiatomaceous earth, and concentrated in vacuo. Chromatography on SiO₂ (5to 40% EtOAc/hexanes) afforded 0.05 g of the desired compound. TLC(SiO₂, 25% EtOAc/hexanes): R_(f)=0.49.

Step E.1-Benzyl-3-(4-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.To a stirred solution of the compound from step D (0.05 g) in 2 mL ofCH₂Cl₂ was added 2.0 mL of TFA. The mixture was stirred at RT for 2 hand concentrated in vacuo. The crude product was re-dissolved in CH₂Cl₂and treated with Dowex® 550A resin. After stirring for 2 h, the mixturewas filtered and concentrated in vacuo to afford 0.04 g of the titlecompound. The product was dissolved in Et₂O and treated with excess 1.0M HCl in Et₂O for 30 min. The solvent was removed in vacuo to afford0.05 g of the corresponding HCl salt. MS (ESI): exact mass calculatedfor C₂₁H₂₀F₃N₃, 371.16; found, m/z 372.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): 7.78-7.74 (m, 4H), 7.37-7.28 (m, 3H), 7.20 (t, J=6.9 Hz, 2H),5.46 (br s, 2H), 4.65 (br s, 1H), 3.40-3.37 (m, 3H), 3.17-3.10 (m, 4H).

The title compounds of Examples 44-53 were prepared according to thegeneral procedure indicated by Example 43, Steps D and E, unlessotherwise noted.

Example 44

1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.07 g) was prepared from the compound of Example43, Step C (0.16 g), and 0.05 g of phenylboronic acid. MS (ESI): exactmass calculated for C₂₀H₂₁N₃, 303.17; found, m/z 304.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.56-7.54 (m, 2H), 7.51-7.43 (m, 3H), 7.39-7.36 (m,2H), 7.33-7.29 (m, 1H), 7.21 (d, J=6.9 Hz, 2H), 5.50 (s, 2H), 3.43-3.38(m, 4H), 3.22-3.20 (m, 2H), 3.12-3.10 (m, 2H).

Example 45

1-Benzyl-3-(2-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.06 g) was prepared from the compound of Example43, Step C (0.31 g), and 0.10 g of 2-fluorophenylboronic acid, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₀H₂₀FN₃, 321.16; found, m/z 322.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.52-7.46 (m, 2H), 7.38-7.18 (m, 7H), 5.46 (s, 2H), 3.38-3.33 (m, 4H),3.17-3.15 (m, 2H), 2.91-2.89 (m, 2H).

Example 46

1-Benzyl-3-(3-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.07 g) was prepared from the compound of Example43, Step C (0.30 g), and 0.10 g of 3-fluorophenylboronic acid, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₀H₂₀FN₃, 321.16; found, m/z 322.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):7.52-7.47 (m, 1H), 7.38-7.27 (m, 5H), 7.20-7.13 (m, 3H), 5.47 (s, 2H),3.43-3.34 (m, 4H), 3.23-3.06 (m, 4H).

Example 47

1-Benzyl-3-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.07 g) was prepared from the compound of Example43, Step C (0.22 g), and 0.20 g of 4-fluorophenylboronic acid, adding9.1 mg of dppf and using 1,4-dioxane as the solvent. MS (ESI): exactmass calculated for C₂₀H₂₀FN₃, 321.16; found, m/z 322.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.54-7.51 (m, 2H), 7.33-7.30 (m, 2H), 7.28-7.24 (m,1H), 7.12-7.07 (m, 4H), 5.35 (s, 2H), 2.98-2.95 (m, 2H), 2.94-2.92 (m,2H), 2.80-2.77 (m, 2H), 2.76-2.74 (m, 2H).

Example 48

1-Benzyl-3-(2,3-difluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.05 g) was prepared from the compound of Example43, Step C (0.30 g), and 0.11 g of 3,4-difluorophenylboronic acid, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₀H₁₉F₂N₃, 339.15; found, m/z 340.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.37-7.26 (m, 6H), 7.21-7.18 (m, 2H), 5.46 (s, 2H), 3.38-3.34 (m, 4H),3.18-3.16 (m, 2H), 2.92-2.90 (m, 2H).

Example 49

1-Benzyl-3-(3,4-dichloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.02 g) was prepared from the compound of Example43, Step C (0.17 g), and 0.08 g of 3,4-dichlorophenylboronic acid. MS(ESI): exact mass calculated for C₂₀H₁₉Cl₂N₃, 371.10; found, m/z 372.1[M+H]⁺, 374.1 [M+H]⁺, 376.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.78-7.74(m, 4H), 7.37-7.28 (m, 3H), 7.21-7.18 (m, 2H), 5.46-5.45 (m, 2H),3.40-3.30 (m, 4H), 3.17-3.10 (m, 4H).

Example 50

1-[4-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-ethanone

The title compound (0.02 g) was prepared from the compound of Example43, Step C (0.20 g), and 0.08 g of 4-acetylphenylboronic acid, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₂H₂₃N₃O, 345.18; found, m/z 346.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):8.10-8.09 (m, 2H), 7.71-7.70 (m, 2H), 7.38-7.19 (m, 5H), 5.48 (s, 2H),3.40 (br s, 4H), 3.28-3.10 (m, 4H), 2.64 (s, 3H).

Example 51

1-Benzyl-3-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.03 g) was prepared from the compound of Example43, Step C (0.26 g), and 0.13 g of 4-trifluoromethoxyphenylboronic acid,using 1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₁H₂₀F₃N₃O, 387.16; found, m/z 388.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.67-7.63 (m, 2H), 7.39-7.28 (m, 5H), 7.20-7.17 (m, 2H), 5.44 (s, 2H),3.39-3.36 (m, 2H), 3.32-3.30 (m, 2H), 3.15-3.06 (m, 4H).

Example 52

1-Benzyl-3-(3-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.04 g) was prepared from the compound of Example43, Step C (0.20 g), and 0.07 g of 3-chlorophenylboronic acid, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₀H₂₀ClN₃, 337.13; found, m/z 338.1 [M+H]⁺, 340.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.56 (br s, 1H), 7.47-7.29 (m, 6H), 7.29-7.19 (m, 2H), 5.44(s, 2H), 3.38-3.36 (m, 2H), 3.32-3.30 (m, 2H), 3.19-3.06 (m, 4H).

Example 53

3-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

The title compound (0.04 g) was prepared from the compound of Example43, Step C (0.30 g), and 0.10 g of 3-cyanophenylboronic acid, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₂₁H₂₀N₄, 328.17; found, m/z 329.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.91-7.86 (m, 2H), 7.76-7.75 (m, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.37-7.20(m, 3H), 7.19-7.18 (m, 2H), 5.45 (s, 2H), 3.39-3.37 (m, 4H), 3.17-3.08(m, 4H).

Example 54

4-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

To a solution of1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 43, Step C; 0.30 g) in 9 mL of1,4-dioxane was added 0.20 g of K₃PO₄, 0.10 g of 4-cyanophenylboronicacid, and 0.05 g of PdCl₂dppf. The mixture was heated at reflux for 72h. The mixture was filtered through diatomaceous earth and concentratedin vacuo to give 0.33 g of an orange solid. Chromatography on SiO₂ (5 to30% EtOAc/hexanes) afforded 0.21 g of a 7:1 mixture of1-benzyl-3-(4-cyano-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester and a side product,1-benzyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acidtert-butyl ester. The mixture of compounds (0.21 g) was dissolved in 7mL CH₂Cl₂ and 7 mL of TFA was added. The mixture was stirred at RT for 1h and concentrated in vacuo. The crude product was dissolved in CH₂Cl₂and treated with Dowex® 550A resin. After stirring for 2 h, the mixturewas filtered and concentrated in vacuo. Chromatography using a C₁₈reverse phase column afforded 0.14 g of the title compound as its TFAsalt. MS (ESI): exact mass calculated for C₂₁H₂₀N₄, 328.17; found, m/z329.1 [M+H]⁺, 351.1 [M+Na]⁺. ¹H NMR (500 MHz, CD₃OD): 7.83-7.81 (m, 2H),7.76-7.74 (m, 2H), 7.36-7.28 (m, 3H), 7.19-7.17 (m, 2H), 5.46 (s, 2H),3.39-3.37 (m, 4H), 3.15-3.09 (m, 4H).

Example 55

1-(4-Chloro-benzyl)-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.1-(4-Chloro-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of 0.13 g of1-(4-chloro-benzyl)-3-trifluoromethanesulfonyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester, prepared as in Example 43, Steps A through C, in3 mL of THF was added 300 μL of water, 0.11 g of K₂CO₃, 44.9 mg ofphenylboronic acid, and 20.0 mg of PdCl₂dppf. The mixture was heated at100° C. for 18 h. The mixture was filtered through diatomaceous earthand concentrated in vacuo. Chromatography on SiO₂ (hexanes to 45%EtOAc/hexanes) afforded 16.1 mg of the desired compound. MS (ESI): exactmass calculated for C₂₅H₂₈ClN₃O₂, 437.19; found, m/z 438.2 [M+H]⁺.

Step B. The above compound (16.1 mg) was converted to the title compound(7.1 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₂₀H₂₀ClN₃, 337.13; found, m/z 338.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.57-7.54 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.31 (m, 1H), 7.30-7.26 (m,3H), 7.04 (d, J=8.5 Hz, 2H), 5.32 (s, 2H), 2.99-2.93 (m, 4H), 2.85-2.82(m, 2H), 2.77-2.73 (m, 2H), 1.97 (br s, 1H).

Example 56

1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of 142.7 mg of1-(4-chloro-benzyl)-3-trifluoromethanesulfonyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester, prepared as in Example 43, Steps A through C, in3 mL of THF was added 0.17 g of K₃PO₄, 54.9 mg of 4-chlorophenylboronicacid, and 22.1 mg of PdCl₂dppf. The mixture was heated at reflux for 48h. The mixture was filtered through diatomaceous earth, rinsing withtoluene, and the filtrate was concentrated in vacuo. Chromatography onSiO₂ (hexanes to 75% EtOAc/hexanes) afforded 6.7 mg of the desiredcompound. MS (ESI): exact mass calculated for C₂₅H₂₇Cl₂N₃O₂, 471.15;found, m/z 472.1 [M+H]⁺.

Step B. The above compound (6.7 mg) was converted to the title compound(5.0 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₂₀H₁₉Cl₂N₃, 371.10; found, m/z 372.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.48 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H),7.03 (d, J=8.5 Hz, 2H), 5.30 (s, 2H), 3.02-2.96 (m, 4H), 2.84-2.80 (m,2H), 2.79-2.76 (m, 2H).

Example 57

1-Benzyl-3-phenyl-6-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.05 g) was prepared from1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example44, 0.09 g) and 23 μL of propionaldehyde as in Example 35. MS (ESI):exact mass calculated for C₂₃H₂₇N₃, 345.22; found, m/z 346.3 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): 7.56-7.54 (m, 2H), 7.47-7.28 (m, 6H), 7.21-7.19(m, 2H), 5.44 (s, 2H), 3.70-3.66 (m, 2H), 3.41-3.07 (m, 8H), 1.86-1.76(m, 2H), 1.03 (t, J=7.3 Hz, 3H).

Example 58

1-Benzyl-6-isopropyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.03 g) was prepared from1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example44, 0.07 g) and 22 μL of acetone as in Example 35. MS (ESI): exact masscalculated for C₂₃H₂₇N₃, 345.22; found, m/z 346.3 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.57-7.52 (m, 2H), 7.50-7.27 (m, 6H), 7.22-7.20 (m, 2H),5.47 (s, 2H), 3.77-3.61 (m, 3H), 3.29-3.28 (m, 3H), 3.24-3.08 (m, 3H),1.40 (d, J=6.0 Hz, 6H).

Example 59

1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. 5-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethylester. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(35 mmol, 7.0 g) in anhydrous Et₂O (50 mL) was stirred in a 200 mL3-neck flask equipped with two addition funnels. The solution was cooledto −25° C. Ethyl diazoacetate (46.5 mmol, 4.89 mL) in anhydrous Et₂O (10mL) and BF₃.OEt₂ (36.7 mmol, 4.65 mL) in anhydrous Et₂O (10 mL) weresimultaneously but independently added to the solution over 90 min. Themixture was stirred for an additional 1 h and was slowly warmed to RT.Then, 30% aq. K₂CO₃ was added dropwise to the mixture until gasevolution ceased. The organic layer was separated, dried over Na₂SO₄,and concentrated. The residue was purified via chromatography (SiO₂, 5to 20% EtOAc/hexanes) to yield the desired compound (7.5 g).

Step B. 4-Oxo-azepane-1-carboxylic acid tert-butyl ester. To a solutionof the product of Step A in 1,4-dioxane (50 mL) was added 1 N NaOH(40.83 mmol, 40.83 mL). The mixture was allowed to stir at rt overnight.The solution was then acidified to pH 4-5 with 3 N HCl. The mixture wasextracted with Et₂O followed by CH₂Cl₂ until TLC showed no productremaining in the aqueous layer. The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo to yield the desired compound(7.46 g). MS (ESI): exact mass calculated for C₁₁H₁₉NO₃, 213.14; found,m/z 236.2 [M+Na]⁺.

Step C.3-(4-Chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. p-Toluenesulfonic acid (0.033 mg, 0.18 mmol) andmorpholine (3.4 mL, 38 mmol) were added to a solution of the product ofstep B (7.46 g, 35.0 mmol) in benzene (15 mL). The reaction mixture washeated at reflux for 20 h using a Dean-Stark trap. The reaction mixturewas cooled to RT and concentrated in vacuo to afford the intermediateenamine, which was used without further purification. To a 0° C.solution of the enamine in CH₂Cl₂ (30 mL) was added triethylamine (27.5mmol, 3.80 mL) followed by a solution of 4-chlorobenzoyl chloride (27.5mmol, 3.50 mL) in CH₂Cl₂ (10 mL). The reaction mixture was allowed towarm to RT and was stirred for 16 h. The mixture was poured over waterand the layers were separated. The organic layer was dried over Na₂SO₄and concentrated. The resulting oil was diluted with EtOH (120 mL),cooled to 0° C., and treated with hydrazine (75 mmol, 2.4 mL). Thereaction mixture was allowed to warm to RT and was stirred for 16 h. Themixture was concentrated and the residue was purified by SFCpurification to yield the desired compound (1.2 g). MS (ESI): exact masscalculated for C₁₈H₂₂ClN₃O₂, 347.14; found, m/z 346.0 [M−H]⁻. ¹H NMR(500 MHz, CD₃OD): 7.40-7.35 (m, 4H), 3.62-3.59 (m, 2H), 3.54-3.51 (m,2H), 2.96-2.93 (m, 2H), 2.81-2.77 (m, 2H), 1.20 (s, 9H). The reactionsequence also yielded3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (1.5 g). MS (ESI): exact mass calculated forC₁₈H₂₂ClN₃O₂, 347.14; found, m/z 346.0 [M−H]⁻. ¹H NMR (500 MHz, CD₃OD):7.65. (d, J=8.2 Hz, 1H), 7.47-7.41 (m, 3H), 4.67-4.45 (m, 2H), 3.71-3.65(m, 2H), 2.90-2.89 (m, 2H), 1.90-1.87 (m, 2H), 1.18 (s, 9H).

Step D.1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a 0° C. solution of the product from Step C(0.10 g, 0.29 mmol) in DMF (2 mL) was added NaH (60% dispersion in oil,92 mg, 2.3 mmol). The solution was allowed to warm to RT over 1 h, and,benzyl chloride (2.3 mmol) was then added. The reaction mixture wasstirred for 16 h and then concentrated. The residue was diluted withwater and extracted with CH₂Cl₂. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated. The crude product waspurified via SiO₂ chromatography to give the desired ester, which wascarried directly into the next step. Also obtained was2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. MS (ESI): exact mass calculated for C₂₅H₂₈ClN₃O₂,437.19; found, m/z 438.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.50-7.48 (m,2H), 7.40-7.38, (m, 2H), 7.33-7.26 (m, 3H), 7.13-7.11 (m, 2H), 5.33 (s,2H), 3.55-3.51 (m, 4H), 2.86-2.77 (m, 4H), 1.47 (s, 9H).

Step E. The product from Step D was dissolved in 9:1 CH₂Cl₂/MeOH (4 mL).An excess of 1 N HCl in Et₂O was added and the resulting mixture wasstirred for 2 h. The progress of the reaction was monitored by MS untilno more starting material was evident. The reaction mixture wasconcentrated to obtain the desired product (51 mg). MS (ESI): exact masscalculated for C₂₀H₂₀ClN₃, 337.13; found, m/z 338.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.56-7.53 (m, 2H), 7.51-7.48 (m, 2H), 7.38-7.29 (m, 3H),7.20-7.19 (m, 2H), 5.48 (s, 2H), 3.42-3.37 (m, 4H), 3.20-3.18 (m, 2H),3.10-3.08 (m, 2H).

An alternative method as outlined in Scheme 5 is shown below:

Step F. 3-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-[1,3]dioxolane.The desired compound (5.0 g) was prepared from 5.0 g of1,4-dioxa-spiro[4.5]decan-8-one, 4.5 mL of 4-chloro-benzoyl chloride and3.0 mL of hydrazine according to the procedure outlined in Step C above.¹H NMR (500 MHz, CDCl₃): 7.53-7.50 (m, 2H), 7.36-7.33 (m, 2H), 4.02 (s,4H), 2.91 (s, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.01 (t, J=6.6 Hz, 2H).

Step G.1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-[1,3]dioxolane.The desired compound (3.93 g) was prepared from 4.0 g of the compoundfrom step F as outlined in Step D, using benzyl bromide (1.9 mL) inplace of benzyl chloride and K₂CO₃ (6.1 g) in place of NaH. ¹H NMR (500MHz, CDCl₃): 7.67-7.64 (m, 2H), 7.39-7.27 (m, 5H), 7.21-7.18 (m, 2H),5.29 (s, 2H), 4.05-3.98 (m, 4H), 2.95 (s, 2H), 2.71 (t, J=6.6 Hz, 2H),1.98 (t, J=6.6 Hz, 2H).

Step H. 1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-oneoxime. A solution of 3.87 g of the compound from step G in 80 mL of THFwith 5 mL of 1 M HCl was heated at reflux for 16 h. The volatiles wereremoved in vacuo and water was added (300 mL). The mixture was adjustedto pH 9 by the addition of 1 M NaOH and then was extracted with CH₂Cl₂.The combined extracts were washed with brine and the solvent was removedin vacuo to provide1-benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one. Thisproduct (3.13 g) was treated with hydroxylamine hydrochloride (3.0 g) in20 mL of pyridine. The reaction mixture was stirred at RT for 14 h thenwas diluted with water (300 mL), and stirred an additional hour. Themixture was filtered on paper and the solids were washed with EtOAc anddried in vacuo to afford 2.48 g of the desired compound. ¹H NMR (500MHz, acetone-d₆): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H),6.91-9.87 (m, 2H), 6.85-6.81 (m, 1H), 6.77-6.73 (m, 2H), 4.87 (s, 2H),3.21 (s, 2H), 2.31 (t, J=6.6 Hz, 2H), 2.09 (t, J=6.6 Hz, 2H).

Step I.1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.A solution of the compound from step H (78.2 mg) in 15 mL of CH₂Cl₂ wascooled to 0° C. and diisobutylaluminum hydride (1.5 M in toluene, 0.75mL) was added. The mixture was allowed to warm to RT and was stirred for12 h. Water (0.2 mL) and NaF (0.40 g) were added and the mixture wasstirred for 1 h. The mixture was filtered through diatomaceous earth andthe filtrate was concentrated to afford 66.7 mg of a mixture of thetitle compound and1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene.MS (ESI): exact mass calculated for C₂₀H₂₀ClN₃, 337.13; found, m/z 338.0[M+H]⁺.

Example 60 through 102 were prepared using the procedures described inExample 59, Steps D and E, unless otherwise noted.

Example 60

1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.068 g) was prepared as in Example 59, Steps D andE, starting with3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (0.1 g), the isomer from Example 59, Step C. Thereaction sequence also yielded2-benzyl-3-(4-chloro-phenyl)-2,6,7,8-tetrahydro-4H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester. MS (ESI): exact mass calculated for C₂₀H₂₀ClN₃,337.13; found, m/z 338.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.51-7.30 (m,4H), 7.37-7.29 (m, 3H), 7.29-7.21 (m, 3H), 5.45 (s, 2H), 4.32 (s, 2H),3.53-3.50 (m, 2H), 3.06-3.03 (m, 2H), 2.04-1.99 (m, 2H).

Example 61

3-(4-Chloro-phenyl)-1-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.028 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using methyl iodide(0.21 mL) in place of benzyl chloride. The reaction sequence alsoyielded3-(4-chloro-phenyl)-2-methyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₄H₁₆ClN₃, 261.10; found, m/z 262.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.69-7.65 (m, 4H), 4.07 (s, 3H), 3.69-3.67 (m, 2H),3.58-3.56 (m, 2H), 3.44-3.42 (m, 2H), 3.05-3.04 (m, 2H).

Example 62

3-(4-Chloro-phenyl)-2-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.011 g) was prepared from3-(4-chloro-phenyl)-2-methyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 61) according to Example 59, Step E. MS(ESI): exact mass calculated for C₁₄H₁₆ClN₃, 261.10; found, m/z 262.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.48-7.45 (m, 2H), 7.28-7.26 (m, 2H),3.60 (s, 3H), 3.31-3.29 (m, 2H), 3.21 (m, 2H), 3.04-3.02 (m, 2H),2.72-2.70 (m, 2H).

Example 63

3-(4-Chloro-phenyl)-1-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.035 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using ethyl iodide(0.27 mL) in place of benzyl chloride. The reaction sequence alsoyielded3-(4-chloro-phenyl)-2-ethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₅H₁₈ClN₃, 275.12; found, m/z 276.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.39-7.34 (m, 4H), 7.11 (q, J=7.3 Hz, 2H), 3.38-3.36 (m,2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.94-2.92 (m, 2H), 1.30 (t,J=7.3 Hz, 3H).

Example 64

3-(4-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.021 g) was prepared from3-(4-chloro-phenyl)-2-ethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 63) according to Example 59, Step E. MS(ESI): exact mass calculated for C₁₅H₁₈ClN₃, 275.12; found, m/z 276.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.46 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6Hz, 2H), 3.90 (q, J=7.2 Hz, 2H), 3.31-3.29 (m, 2H), 3.20-3.19 (m, 2H),3.06-3.04 (m, 2H), 2.69-2.67 (m, 2H), 1.17 (t, J=7.2 Hz, 3H).

Example 65

3-(4-Chloro-phenyl)-1-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.031 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 1-iodopropane(0.33 mL) in place of benzyl chloride. The reaction sequence alsoyielded3-(4-chloro-phenyl)-2-propyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₆H₂₀ClN₃, 289.13; found, m/z 290.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.39-7.35 (m, 4H), 4.03 (t, J=7.2 Hz, 2H), 3.37-3.35 (m,2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.95-2.93 (m, 2H), 1.76-1.69(m, 2H), 0.84 (t, J=7.4 Hz, 3H).

Example 66

3-(4-Chloro-phenyl)-2-propyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.016 g) was prepared from3-(4-chloro-phenyl)-2-propyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 65) according to Example 59, Step E. MS(ESI): exact mass calculated for C₁₆H₂₀ClN₃, 289.13; found, m/z 290.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.45 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.30-3.28 (m, 2H), 3.20-3.19 (m, 2H),3.05-3.03 (m, 2H), 2.68-2.66 (m, 2H), 1.62-1.18 (m, 2H), 0.65 (t, J=7.4Hz, 3H).

Example 67

1-Butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.033 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 1-iodobutane(0.038 mL) in place of benzyl chloride. The reaction sequence alsoyielded2-butyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₇H₂₂ClN₃, 303.15; found, m/z 304.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.39-7.34 (m, 4H), 4.07 (t, J=7.2 Hz, 2H), 3.37-3.35 (m,2H), 3.27-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95-2.92 (m, 2H), 1.69-1.66(m, 2H), 1.22-1.20 (m, 2H), 0.86 (t, J=7.4 Hz, 3H).

Example 68

2-Butyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.018 g) was prepared from2-butyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 67) according to Example 59, Step E. MS(ESI): exact mass calculated for C₁₇H₂₂ClN₃ 303.15; found, m/z 304.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.46 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4Hz, 2H), 3.91-3.88 (m, 2H), 3.32-3.30 (m, 2H), 3.21-3.19 (m, 2H),3.07-3.05 (m, 2H), 2.70-2.68 (m, 2H), 1.58-1.52 (m, 2H), 1.06-1.03 (m,2H), 0.68 (t, J=7.4 Hz, 3H).

Example 69

3-(4-Chloro-phenyl)-1-(2-cyclohexyl-ethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.056 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using1-bromo-2-cyclohexylethane (0.053 mL) in place of benzyl chloride. Thereaction sequence also yielded3-(4-chloro-phenyl)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₈ClN₃, 357.20; found, m/z 358.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.46-7.34 (m, 4H), 4.08 (t, J=7.6 Hz, 2H), 3.37-3.35 (m,2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.94-2.92 (m, 2H), 1.68-1.20(m, 7H), 1.18-1.05 (m, 4H), 0.93-0.86 (m, 2H).

Example 70

3-(4-Chloro-phenyl)-2-(2-cyclohexyl-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.026 g) was prepared from3-(4-chloro-phenyl)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 69) according to Example 59, Step E. MS(ESI): exact mass calculated for C₂₁H₂₈ClN₃, 357.20; found, m/z 358.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.46 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 3.90 (t, J=7.3 Hz, 2H), 3.30-3.28 (m, 2H), 3.20-3.19 (m, 2H),3.05-3.03 (m, 2H), 2.69-2.67 (m, 2H), 1.48-1.41 (m, 5H), 1.36-1.33 (m,2H), 1.03-1.00 (m, 3H), 0.95-0.89 (m, 1H), 0.81-0.67 (m, 2H).

Example 71

3-(4-Chloro-phenyl)-1-phenethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.048 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using(2-chloroethyl)benzene (0.045 mL) in place of benzyl chloride. Thereaction sequence also yielded3-(4-chloro-phenyl)-2-phenethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.52-7.47 (m, 4H), 7.28-7.21 (m, 3H), 7.03-7.01 (m, 2H),4.39 (t, J=6.4 Hz, 2H), 3.20-3.18 (m, 2H), 3.13-3.10 (m, 2H), 2.95-2.93(m, 2H), 2.91-2.89 (m, 2H), 2.69-2.67 (m, 2H).

Example 72

3-(4-Chloro-phenyl)-2-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.020 g) was prepared from3-(4-chloro-phenyl)-2-phenethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 71) according to Example 59, Step E. MS(ESI): exact mass calculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.38-7.36 (m, 2H), 7.19-7.14 (m, 3H),6.83-6.79 (m, 4H), 4.14 (t, J=6.7 Hz, 2H), 3.41-3.39 (m, 2H), 3.26-3.24(m, 2H), 3.19-3.17 (m, 2H), 3.01-2.98 (m, 2H), 2.69-2.67 (m, 2H).

Example 73

3-(4-Chloro-phenyl)-1-(4-fluoro-3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.002 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride. MS(ESI): exact mass calculated for C₂₁H₂₁ClFN₃, 369.14; found, m/z 370.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.49-7.47 (m, 2H), 7.45-7.42 (m, 2H),7.07-7.01 (m, 1H), 7.00-6.95 (m, 1H), 6.95-6.90 (m, 1H), 5.31 (s, 2H),2.97-2.91 (m, 4H), 2.89-2.84 (m, 2H), 2.82-2.77 (m, 2H), 2.22 (s, 3H).

Example 74

3-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.004 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-methylbenzylchloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact masscalculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.99 (t, J=7.5 Hz,1H), 6.88 (d, J=7.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J=7.1 Hz, 1H), 5.13(s, 2H), 2.79-2.73 (m, 4H), 2.69-2.65 (m, 2H), 2.63-2.60 (m, 2H), 2.09(s, 3H).

Example 75

3-(4-Chloro-phenyl)-1-(4-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.003 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 4-fluorobenzylchloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact masscalculated for C₂₀H₁₉ClFN₃, 355.13; found, m/z 356.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.40-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.08-7.04 (m, 2H),6.98-6.94 (m, 2H), 5.26 (s, 2H), 2.89-2.86 (m, 4H), 2.80-2.78 (m, 2H),2.73-2.70 (m, 2H).

Example 76

3-(4-Chloro-phenyl)-1-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.01 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-fluorobenzylchloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact masscalculated for C₂₀H₁₉ClFN₃, 355.13; found, m/z 356.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.42-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.28-7.21 (m, 1H),6.93-6.88 (m, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.75-6.71 (m, 1H), 5.29 (s,2H), 2.89-2.85 (m, 4H), 2.79-2.76 (m, 2H), 2.74-2.70 (m, 2H).

Example 77

3-(4-Chloro-phenyl)-1-(4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.013 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.74 g) using 4-methylbenzylchloride (0.45 g) in place of benzyl chloride. The reaction sequencealso yielded3-(4-chloro-phenyl)-2-(4-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.39-7.36 (m, 2H), 7.34-7.31 (m, 2H), 7.03 (d, J=8.0 Hz,2H), 6.90 (d, J=8.0 Hz, 2H), 5.21 (s, 2H), 2.83-2.67 (m, 4H), 2.75-2.72(m, 2H), 2.69-2.67 (m, 2H), 2.20 (s, 3H).

Example 78

3-(4-Chloro-phenyl)-1-(3,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.002 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester(Example 59, Step C; 0.07 g) using 3,4-difluorobenzyl bromide (0.4 mL)in place of benzyl chloride. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(3,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₁₈ClF₂N₃, 373.12; found, m/z 374.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.22-7.20 (m,1H), 7.07-7.02 (m, 1H), 6.96-6.92 (m, 1H), 5.26 (s, 2H), 3.06-3.02 (m,4H), 2.94-2.91 (m, 2H), 2.87-2.84 (m, 2H).

Example 79

3-(4-Chloro-phenyl)-1-(3-nitro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.005 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-nitrobenzylbromide (0.09 g) in place of benzyl chloride and Cs₂CO₃ (0.2 g) in placeof NaH. MS (ESI): exact mass calculated for C₂₀H₁₉ClN₄O₂, 382.12; found,m/z 383.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.07-8.05 (m, 1H), 7.91-7.87(m, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.44-7.38 (m, 3H), 7.36-7.33 (m, 2H),5.41 (s, 2H), 2.88-2.85 (m, 4H), 2.82-2.79 (m, 2H), 2.73-2.71 (m, 2H).

Example 80

3-(4-Chloro-phenyl)-1-(3-fluoro-4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.003 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using3-fluoro-4-methylbenzyl bromide (0.9 g) in place of benzyl chloride. MS(ESI): exact mass calculated for C₂₁H₂₁ClFN₃, 369.14; found, m/z 370.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.50-7.47 (m, 2H), 7.44-7.42 (m, 2H),7.19 (t, J=7.6 Hz, 1H), 6.84-6.81 (m, 1H), 6.78-6.75 (m, 1H), 5.33 (s,2H), 2.95-2.92 (m, 4H), 2.87-2.84 (m, 2H), 2.81-2.78 (m, 2H), 2.22 (s,3H).

Example 81

3-(4-Chloro-phenyl)-1-(3,4-dimethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.003 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using3,4-dimethylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS(ESI): exact mass calculated for C₂₂H₂₄ClN₃, 365.17; found, m/z 366.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.40-7.38 (m, 2H), 7.35-7.32 (m, 2H),6.98-6.96 (m, 1H), 6.90-6.86 (m, 1H), 6.72-6.69 (m, 1H), 5.30 (s, 1H),5.19 (s, 1H), 2.90-2.87 (m, 2H), 2.86-2.82 (m, 2H), 2.77-2.73 (m, 2H),2.72-2.68 (m, 2H), 2.21 (s, 3H), 2.17 (s, 3H).

Example 82

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoicacid methyl ester

The title compound (0.0042 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.15 g) using methyl5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reactionsequence also yielded3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in thealkylation step. MS (ESI): exact mass calculated for C₁₉H₂₄ClN₃O₂,361.16; found, m/z 362.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.54-7.51 (m,2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01(m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H),1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).

Example 83

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoicacid

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoicacid methyl ester (Example 82, 0.009 g) was dissolved in 1 mL of 9:1THF/MeOH and treated with 2 mL of 1 M NaOH. After stirring at RT for 5h, the solvent was removed in vacuo. The aqueous residue was acidifiedwith 1 mL of 1 N HCl and the mixture was extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, concentrated, and driedon a vacuum line. The residue was then dissolved in 1 mL of 9:1CH₂Cl₂/MeOH and treated with 3 mL of 1 N HCl in Et₂O. After 4 h, thevolatiles were removed in vacuo. The crude oil was purified bypreparative TLC (9:1 CH₂Cl₂/2 M NH₃ in MeOH) to afford 0.002 g of thetitle compound. MS (ESI): exact mass calculated for C₁₈H₂₂ClN₃O₂,347.14; found, m/z 348.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.55-7.53 (m,4H), 7.35-7.32 (m, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.38-3.35 (m, 2H),3.28-3.26 (m, 2H), 3.13-3.10 (m, 2H), 2.77-2.74 (m, 2H), 2.09-2.06 (m,2H), 1.71-1.66 (m, 2H), 1.41-1.37 (m, 2H).

Example 84

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentan-1-ol

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoicacid methyl ester (Example 82, 0.009 g) was dissolved in 9:1 Et₂O/CH₂Cl₂(3 mL) and the solution was added slowly to a stirred suspension oflithium aluminum hydride (2 mg) in 5 mL of anhydrous Et₂O. Afterstirring at RT for 6 h, the reaction was quenched with 2 mL of water.The mixture was treated with 2 mL of 1 N NaOH, followed by another 2 mLof water. The mixture was then filtered through diatomaceous earth. Theorganic layer was separated, dried over MgSO₄, and concentrated. Afterfurther drying via vacuum line, the resulting oil was dissolved in 2 mLof 9:1 CH₂Cl₂/MeOH and treated with 3 mL of 1 N HCl in Et₂O. After 4 h,the volatiles were removed in vacuo. The crude oil was purified bypreparative TLC (9:1 CH₂Cl₂/2 M NH₃ in MeOH) to afford 0.001 g of thetitle compound as a colorless oil. MS (ESI): exact mass calculated forC₁₈H₂₄ClN₃O, 333.16; found, m/z 334.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.54-7.52 (m, 2H), 7.32-7.30 (m, 2H), 3.95 (t, J=7.1 Hz, 2H), 3.44 (t,J=6.6 Hz, 2H), 3.13-3.09 (m, 2H), 3.03-3.00 (m, 2H), 2.98-2.95 (m, 2H),2.61-2.58 (m, 2H), 1.70-1.64 (m, 2H), 1.40-1.35 (m, 2H), 1.20-1.16 (m,2H).

Example 85

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoicacid methyl ester

The title compound (0.0051 g) was prepared from3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 82) according to Example 59, Step E. MS(ESI): exact mass calculated for C₁₉H₂₄ClN₃O₂, 361.16; found, m/z 362.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.45-7.40 (m, 4H), 4.13 (t, J=7.0 Hz,2H), 3.63 (s, 3H), 3.04-3.03 (m, 2H), 2.97-2.95 (m, 4H), 2.79-2.76 (m,2H), 2.34 (t, J=7.4 Hz, 2H), 1.81-1.77 (m, 2H), 1.61-1.58 (m, 2H).

Example 86

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoicacid

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoicacid methyl ester (Example 85, 0.014 g) was hydrolyzed and de-protectedas in Example 83 to afford the title compound (0.0014 g). MS (ESI):exact mass calculated for C₁₈H₂₂ClN₃O₂, 347.14; found, m/z 348.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.49-7.43 (m, 4H), 4.18 (t, J=7.0 Hz, 2H),3.45-3.43 (m, 2H), 3.25-3.22 (m, 2H), 3.17-3.16 (m, 2H), 3.04-3.01 (m,2H), 2.28-2.24 (m, 2H), 1.84-1.82 (m, 2H), 1.60-1.57 (m, 2H).

Example 87

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentan-1-ol

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoicacid methyl ester (Example 85, 0.015 g) was reduced as in Example 84 toafford the title compound (0.0063 g) as a colorless oil. MS (ESI): exactmass calculated for C₁₈H₂₄ClN₃O, 333.16; found, m/z 334.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.45-7.40 (m, 4H), 4.13 (t, J=7.2 Hz, 2H), 3.53 (t,J=6.4 Hz, 2H), 3.04-3.01 (m, 2H), 2.97-2.92 (m, 4H), 2.78-2.75 (m, 2H),1.82-1.75 (m, 2H), 1.57-1.51 (m, 2H), 1.41-1.34 (m, 2H).

Example 88

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyricacid methyl ester

The title compound (0.003 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using methyl4-chlorobutyrate (0.8 mL) in place of benzyl chloride. The reactionsequence also yielded3-(4-chloro-phenyl)-2-(3-methoxycarbonyl-propyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₈H₂₂ClN₃O₂, 347.14; found, m/z 348.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.37-7.31 (m, 4H), 4.07 (t, J=6.6 Hz, 2H), 3.52 (s,3H), 2.97-2.94 (m, 2H), 2.88-2.84 (m, 4H), 2.70-2.66 (m, 2H), 2.25 (t,J=6.6 Hz, 2H), 1.98-1.95 (m, 2H).

Example 89

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyricacid methyl ester

The title compound (0.003 g) was prepared from3-(4-chloro-phenyl)-2-(3-methoxycarbonyl-propyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 88) according to Example 59, Step E. MS(ESI): exact mass calculated for C₁₈H₂₂ClN₃O₂, 347.14; found, m/z 348.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.45-7.42 (m, 2H), 7.23-7.20 (m, 2H),3.91 (t, J=6.9 Hz, 2H), 3.44 (s, 3H), 3.04-3.00 (m, 2H), 2.93-2.86 (m,4H), 2.52-2.49 (m, 2H), 2.07 (t, J=7.0 Hz, 2H), 1.88-1.80 (m, 2H).

Example 90

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyricacid

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyricacid methyl ester (Example 89, 0.006 g) was hydrolyzed as in Example 83to afford the title compound (0.005 g). MS (ESI): exact mass calculatedfor C₁₇H₂₀ClN₃O₂, 333.12; found, m/z 334.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.55-7.52 (m, 2H), 7.35-7.33 (m, 2H), 3.98 (t, J=6.8 Hz, 2H),3.12-3.09 (m, 2H), 3.03-2.96 (m, 4H), 2.62-2.59 (m, 2H), 2.03-1.97 (m,4H).

Example 91

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyricacid

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyricacid methyl ester (Example 88, 0.009 g) was hydrolyzed as in Example 83to afford the title compound (0.003 g). MS (ESI): exact mass calculatedfor C₁₇H₂₀ClN₃O₂, 333.12; found, m/z 334.1[M+H]⁺, m/z 332.0 [M−H]⁻. ¹HNMR (400 MHz, CD₃OD): 7.46-7.44 (m, 4H), 4.17 (t, J=7.1 Hz, 2H),3.11-3.08 (m, 2H), 3.05-2.98 (m, 4H), 2.83-2.79 (m, 2H), 2.18-2.15 (m,2H), 2.07-2.03 (m, 2H).

Example 92

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butan-1-ol

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyricacid methyl ester (Example 89, 0.006 g) was reduced as in Example 84 toafford the title compound as a white solid (0.001 g). MS (ESI): exactmass calculated for C₁₇H₂₂ClN₃O, 319.15; found, m/z 320.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 7.45-7.41 (m, 2H), 7.22-7.20 (m, 2H), 3.89-3.84 (m,2H), 3.32-3.29 (m, 2H), 2.94-2.91 (m, 2H), 2.85-2.81 (m, 4H), 2.47-2.43(m, 2H), 1.63-1.58 (m, 2H), 1.24-1.17 (m, 2H).

Example 93

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butan-1-ol

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyricacid methyl ester (Example 88, 0.02g) was reduced and de-protected as inExample 84 to afford the title compound as a white solid (0.007 g). MS(ESI): exact mass calculated for C₁₇H₂₂ClN₃O, 319.15; found, m/z 320.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.36-7.31 (m, 4H), 4.05 (t, J=7.2 Hz,2H), 3.45 (t, J=6.4 Hz, 2H), 2.96-2.94 (m, 2H), 2.89-2.84 (m, 4H),2.70-2.66 (m, 2H), 1.77-1.68 (m, 2H), 1.46-1.39 (m, 2H).

Example 94

3-(4-Chloro-phenyl)-2-(3,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.001 g) was prepared from3-(4-chloro-phenyl)-2-(3,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 78) according to Example 59, Step E. MS(ESI): exact mass calculated for C₂₀H₁₈ClF₂N₃, 373.12; found, m/z 374.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.41-7.36 (m, 2H), 7.15-7.10 (m, 2H),7.07-7.01 (m, 1H), 6.77-6.72 (m, 1H), 6.65-6.62 (m, 1H), 5.06 (s, 2H),3.17-3.15 (m, 2H), 09-3.05 (m, 2H), 2.99-2.97 (m, 2H), 2.62-2.59 (m,2H).

Example 95

3-(4-Chloro-phenyl)-2-(4-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.005 g) was prepared from3-(4-chloro-phenyl)-2-(4-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 77) according to Example 59, Step E. MS(ESI): exact mass calculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.36-7.33 (m, 2H), 7.10-7.01 (m, 2H),6.95 (d, J=7.8 Hz, 2H), 6.69 (d, J=8.0 Hz, 2H), 5.01 (s, 2H), 2.92-2.90(m, 2H), 2.83-2.80 (m, 4H), 2.46-2.43 (m, 2H), 2.16 (s, 3H).

Example 96

3-(4-Chloro-phenyl)-1-(3-fluoro-4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.021 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.35 g) using3-fluoro-4-methoxybenzyl bromide (0.25 g) in place of benzyl chloride.The reaction sequence also provided3-(4-chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₁ClFN₃O, 385.14; found, m/z 386.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.50-7.47 (m, 2H), 7.47-7.42 (m, 2H), 7.06-7.02 (m,1H), 6.90-6.86 (m, 2H), 5.29 (s, 2H), 3.84 (s, 3H), 3.35-3.29 (m, 2H),2.94-2.92 (m, 4H), 2.88-2.85 (m, 2H), 2.80-2.77 (m, 2H). ¹³C NMR (125MHz, CD₃OD): 154.2, 152.2, 149.1, 148.1, 143.5, 134.2, 132.9, 131.1,131.0, 130.5, 129.1, 123.3, 118.7, 115.0, 114.8, 114.4, 56.2, 52.4,49.9, 28.8, 27.3.

Example 97

3-(4-Chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.017 g) was prepared from3-(4-chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 96) according to Example 59, Step E. MS(ESI): exact mass calculated for C₂₁H₂₁ClFN₃O, 385.14; found, m/z 386.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.48-7.45 (m, 2H), 7.21-7.18 (m, 2H),6.95-6.92 (m, 1H), 6.67-6.63 (m, 2H), 5.08 (s, 2H), 3.81 (s, 3H),3.31-3.30 (m, 2H), 3.01-2.98 (m, 2H), 2.94-2.88 (m, 4H), 2.55-2.52 (m,2H). ¹³C NMR (125 MHz, CD₃OD): 154.9, 153.8, 153.0, 148.9, 142.5, 136.6,133.0, 132.1, 130.5, 130.0, 129.4, 124.3, 120.7, 116.0, 115.8, 115.1,57.1, 53.3, 51.3, 32.7, 28.0.

Example 98

3-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.004 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.3 g) using 4-nitrobenzylbromide (0.3 g) in place of benzyl chloride. MS (ESI): exact masscalculated for C₂₀H₁₉ClN₄O₂, 382.12; found, m/z 383.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 8.23-8.19 (m, 2H), 7.51-7.47 (m, 2H), 7.45-7.47 (m,2H), 7.32 (d, J=8.6 Hz, 2H), 5.52 (s, 2H), 2.98-2.95 (m, 4H), 2.89-2.85(m, 2H), 2.83-2.79 (m, 2H).

Example 99

4-(3-Phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenylamine

3-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 98, 70 mg) was dissolved in 25 mL ofanhydrous EtOH and treated with 10% palladium on carbon (20 mg). Themixture was subjected to hydrogen for 4 h at 30 psi. The mixture wasfiltered through diatomaceous earth. The filtrate was concentrated anddried via vacuum line to afford 55 mg of1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The intermediate aniline was then dissolved in 1mL of MeOH and treated with 5 mL of 1 N HCl in Et₂O. After 6 h, thevolatiles were removed in vacuo. The resulting yellow semi-solid waspurified by preparative TLC (9:1 CH₂Cl₂/2 M NH₃ in MeOH) to afford 0.007g of the title compound as a light yellow solid. MS (ESI): exact masscalculated for C₂₀H₂₂N₄, 318.18; found, m/z 319.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.50-7.47 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.34 (m, 1H),6.94-6.90 (m, 2H), 6.68-6.65 (m, 2H), 5.23 (s, 2H), 3.11-3.06 (m, 4H),2.99-2.96 (m, 2H), 2.91-2.88 (m, 2H).

Example 100

N-[4-(3-Phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-methanesulfonamide

To a solution of 0.022 g of1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99) in DMF (1mL) was added 1 equivalent of triethylamine. After 5 min, 1 equivalentof methanesulfonyl chloride was added and the mixture was stirredovernight. The reaction was quenched with water and extracted with EtOAc(3×). The combined organic layers were dried over Na₂SO₄ andconcentrated. The resulting oil was purified by preparative TLC (50%EtOAc/hexanes) to give1-(4-methanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. This mono-mesylate was then dissolved in 9:1CH₂Cl₂/MeOH (2 mL) and treated with 3 mL of 1 N HCl in Et₂O. After 6 h,the volatiles were removed in vacuo. The resulting oil was purified bypreparative TLC (9:1 CH₂Cl₂/2 M NH₃ in MeOH) to afford 0.004 g of thetitle compound as a white solid. MS (ES!): exact mass calculated forC₂₁H₂₄N₄O₂S, 396.16; found, m/z 397.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.50-7.47 (m, 2H), 7.42 (t, J=7.7 Hz, 2H), 7.37-7.34 (m, 1H), 7.22-7.20(m, 2H), 7.13-7.10 (m, 2H), 5.34 (s, 2H), 2.97-2.93 (m, 4H), 2.92 (s,3H), 2.90-2.87 (m, 2H), 2.82-2.78 (m, 2H).

Example 101

N,N-[4-(3-phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-20dimethanesulfonamide

1-(4-Amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 99, 0.05 mmol) was dissolved in 1 mL ofDMF and treated with 1 equivalent of triethylamine. After 5 min, 1.5equivalents of methanesulfonyl chloride were added and the mixture wasstirred overnight. The reaction was quenched with water and extractedwith EtOAc (3×). The combined organic layers were dried over Na₂SO₄ andconcentrated. The resulting oil was purified by preparative TLC (50%EtOAc/hexanes) to provide1-(4-dimethanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The intermediate was then dissolved in 2 mL of9:1 CH₂Cl₂/MeOH and treated with 3 mL of 1 N HCl in Et₂O. After 6 h, thevolatiles were removed in vacuo. The crude oil was purified bypreparative TLC (9:1 CH₂Cl₂/2 M NH₃ in MeOH) to afford 0.006 g of thetitle compound as an off-white solid. MS (ESI): exact mass calculatedfor C₂₂H₂₆N₄O₄S₂, 474.14; found, m/z 475.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): 7.50-7.47 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.35 (m, 1H),7.22-7.20 (m, 2H), 7.13-7.11 (m, 2H), 5.34 (s, 2H), 2.97-2.94 (m, 4H),2.92 (s, 6H), 2.89-2.87 (m, 2H), 2.82-2.80 (m, 2H).

Example 102

1-Benzyl-3-p-tolyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.2 g) was prepared from 4-oxo-azepane-1-carboxylicacid tert-butyl ester (Example 59, Step B; 10 mmol) as in Example 59,Steps C through E, using 4-methyl-benzoyl chloride (11 mmol) in place of4-chloro-benzoyl chloride. MS (ESI): exact mass calculated for C₂₁H₂₃N₃, 317.19; found, m/z 318.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.34-7.33(m, 2H), 7.29-7.26 (m, 2H), 7.24-7.21 (m, 3H), 7.10-7.09 (m, 2H), 5.40(s, 2H), 3.33-3.27 (m, 4H), 3.11-3.09 (m, 2H), 3.00-2.98 (m, 2H), 2.30(s, 3H).

Example 103

3-(4-Chloro-phenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. 1-(4-Chlorophenyl)-2-diazo-ethanone. To a solution ofdiazomethane (33.2 mmmol) in Et₂O (70 mL) was added triethylamine (33.2mmol). The mixture was cooled to 0° C., and 4-chlorobenzoyl chloride (30mmol) in Et₂O (30 mL) was added slowly. The mixture was then warmed toRT and stirred for 1 h. After filtration of the mixture, the clearfiltrate was concentrated to provide the crude desired compound (5.4 g).

Step B.3-(4-Chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a 0° C. mixture of 4-oxo-piperidine1-carboxylic acid tert-butyl ester (20 mmol) in Et₂O (150 mL) was addeda solution of BF₃.Et₂O (30 mmol) in Et₂O (150 mL) followed by a solutionof the product from Step A (21 mmol) in Et₂O (150 mL). After theaddition was complete, the mixture was warmed to 25° C. and stirred for1 h. Satd. aq. NaHCO₃ (200 mL) was added, and the layers were separated.The organic layer was concentrated, and the resulting residue wasdiluted with MeOH (100 mL). Hydrazine (3 mL) was added and the mixturewas stirred at 25° C. for 16 h. Purification by flash chromatography(EtOAc/CH₂Cl₂) provided the desired compound (1.8 g).

Step C. The product from Step B (0.2 mmol) was mixed with2-chloromethyl-thiophene (0.3 mmol) in DMF (2 mL), and Cs₂CO₃ (0.3 mmol)was then added.

The mixture was stirred at 25° C. for 16 h. After concentration andpurification by SiO₂ chromatography (EtOAc/hexanes),3-(4-chloro-phenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulenewas obtained. The intermediate was treated with TFA (1 mL) in CH₂Cl₂ (10mL) for 4 h. After concentration of the reaction mixture, the titlecompound was obtained (0.029 g). The reaction sequence also provided3-(4-chloro-phenyl)-2-thiophen-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₈H₁₈ClN₃O, 343.09; found, m/z 344.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.46-7.44 (m, 2H), 7.41-7.39 (m, 2H), 7.29 (dd, J=5.1, 1.1Hz, 1H), 7.00 (dd, J=3.5. 1.1 Hz, 1H), 6.91 (dd, J=5.1, 3.5 Hz, 1H),5.52 (s, 2H), 3.36-3.34 (m, 2H), 3.30-3.28 (m, 2H), 3.24-3.18 (m, 2H),2.99-2.97 (m, 2H).

Example 104 through 155 were prepared using the procedure described inExample 103 unless otherwise noted.

Example 104

1-Benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (28 mg) was prepared from3-thiophen-2-yl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester as described in Example 103, usingthiophene-2-carbonyl chloride (5 mmol) in place of 4-chlorobenzoylchloride, and benzyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C₁₈H₁₉N₃S,309.13; found, m/z 310.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.27-7.01 (m,8H), 5.28 (s, 2H), 3.26-3.24 (br m, 2H), 3.18-3.16 (br m, 2H), 3.11-3.09(br m, 2H), 2.96-2.94 (br m, 2H).

Example 105

3-(4-Chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.095 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 1 mmol) using3-methoxy-benzyl chloride (1.5 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₂₁H₂₂ClN₃O, 367.15; found, m/z 368.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.60 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.32 (d, J=7.9 Hz, 1H),6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.84 (s, 1H), 6.80 (d, J=8.2 Hz, 1H), 5.57(s, 2H), 3.79 (s, 3H), 3.48-3.46 (br m, 2H), 3.44-3.42 (br m, 2H),3.33-3.31 (br m, 2H), 3.16-3.14 (br m, 2H).

Example 106

3-(4-Chloro-phenyl)-1-(2-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.042 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2-fluorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₂₀H₁₉ClFN₃, 355.13; found, m/z356.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.55-7.48 (br m, 4H), 7.39-3.37(br m, 1H), 7.20-7.14 (m, 3H), 5.54 (s, 2H), 3.48-3.46 (br m, 2H),3.40-3.38 (br m, 2H), 3.31-3.29 (br m, 2H), 3.13-3.11 (br m, 2H).

Example 107

3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.03 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2-methylbenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene.The reaction sequence also yielded3-(4-chloro-phenyl)-2-(2-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.56 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.23-7.15(m, 3H), 6.58 (d, J=7.5, 1H), 5.50 (s, 2H), 3.42-3.39 (br m, 4H),3.15-3.12 (br m, 4H), 2.40 (s, 3H).

Example 108

3-(4-Chloro-phenyl)-1-(2,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.030 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2,4-difluorobenzyl bromide (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(2,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₁₈ClF₂N₃, 373.12; found, m/z 374.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 7.52-7.49 (br m, 4H), 7.27-7.24 (br m, 1H), 7.01-6.99(br m, 2H), 5.52 (s, 2H), 3.51-3.49 (br m, 2H), 3.43-3.40 (br m, 2H),3.34-3.31 (br m, 2H), 3.11-3.09 (br m, 2H).

Example 109

3-(4-Chloro-phenyl)-1-(2-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.06 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.3 mmol) using2-methoxybenzyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(2-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₂ClN₃O, 367.15; found, m/z 368.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.45-7.43 (m, 2H), 7.30-7.27 (m, 2H), 7.18-7.17 (m, 1H),6.80-6.77 (m, 2H), 6.61-6.59 (m, 1H), 5.26 (s, 2H), 3.80 (s, 3H),2.92-2.86 (m, 4H), 2.74-2.69 (m, 4H).

Example 110

1-(2-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.01 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2-chlorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₁₇H₂₂ClN₃O, 371.10; found, m/z372.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.43-7.41 (m, 2H), 7.32-7.30 (m,2H), 7.32 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.23 (s, 2H),2.94-2.91 (br m, 4H), 2.79-7.77 (br m, 2H), 2.73-7.71 (br m, 2H).

Example 111

1-But-3-enyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.028 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-but-3-enylchloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI):exact mass calculated for C₁₇H₂₂ClN₃O, 301.13; found, m/z 302.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.40-7.37 (m, 2H), 7.31-7.28 (m, 2H), 6.75-6.67(m, 1H), 5.02-5.00 (br m, 2H), 4.07 (t, J=7.3 Hz, 2H), 2.99-2.97 (br m,2H), 2.91-2.89 (br m, 2H), 2.80-2.78 (br m, 2H), 2.71-2.69 (br m, 2H),2.48 (q, J=7.3 Hz, 2H).

Example 112

1-(2-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.035 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₂₀H₁₉BrClN₃, 415.05; found, m/z418.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.69 (d, J=7.8 Hz, 1H), 7.53-7.27(m, 6H), 6.78 (d, J=7.8 Hz, 1H), 5.58 (s, 2H), 3.50-3.48 (br m, 4H),3.19-3.17 (br m, 4H).

Example 113

1-(4-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.032 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.3 mmol) using4-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₂₀H₁₉BrClN₃, 415.05; found, m/z418.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.48-7.40 (m, 6H), 6.92 (d, J=8.4Hz, 2H), 5.28 (s, 2H), 3.32-3.30 (br m, 4H), 3.03-3.01 (br m, 4H).

Example 114

3-(4-Chloro-phenyl)-1-(2-ethyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.010 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using1-bromo-2-ethyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene.The reaction sequence also yielded3-(4-chloro-phenyl)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₉H₂₆ClN₃, 331.18; found, m/z 332.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.50-7.48 (br m, 4H), 4.11-4.09 (br m, 2H), 3.71-3.69 (brm, 2H), 3.33-3.31 (br m, 2H), 3.26-3.24 (br m, 2H), 3.06-3.04 (br m,2H), 1.91-1.89 (m, 1H), 1.36-1.34 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).

Example 115

3-(4-Chloro-phenyl)-1-(5-chloro-thiophen-2-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.029 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using5-chloro-thiophen-2-ylmethyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₈H₁₇O₂N₃S, 377.05; found, m/z 378.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.54-7.51 (m, 2H), 7.49-7.46 (m, 2H), 3.91 (d, J=3.8 Hz,1H), 6.86 (d, J=3.8 Hz, 1H), 5.51 (s, 2H), 3.45-3.44 (m, 2H), 3.38-3.61(m, 2H), 3.27-3.25 (m, 2H), 3.07-3.05 (m, 2H).

Example 116

1-(3-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.04 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using3-bromobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₂₀H₁₉BrClN₃, 415.05; found, m/z416.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.50-6.86 (m, 8H), 5.36 (s, 2H),3.30-3.27 (br m, 4H), 3.06-3.04 (m, 4H).

Example 117

3-(4-Chloro-phenyl)-1-cyclohexylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.09 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 170 mg) usingcyclohexylmethyl bromide (2 mmol) in place of 2-chloromethyl-thiophene.The reaction sequence also yielded3-(4-chloro-phenyl)-2-cyclohexylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₂₆ClN₃, 343.18; found, m/z 344.3 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.37 (d, J=6.6 Hz, 2H), 7.32 (d, J=6.6 Hz, 2H), 3.94 (d,J=7.3 Hz, 2H), 3.44-3.40 (br m, 2H), 3.35-3.32 (br m, 2H), 3.17-3.14 (brm, 2H), 3.01-2.99 (br m, 2H), 1.74-1.53 (m, 4H), 1.52 (d, J=11.2 Hz,2H), 1.17-1.10 (m, 3H), 0.94-0.90 (m, 2H).

Example 118

3-(4-Chloro-phenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.031 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using isobutylbromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reactionsequence also yielded3-(4-chloro-phenyl)-2-isobutyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester from the alkylation step. MS (ESI): exact masscalculated for C₁₇H₂₂ClN₃, 303.15; found, m/z 304.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.64 (d, J=6.6 Hz, 2H), 7.56 (d, J=6.6 Hz, 2H), 4.20 (d,J=7.4 Hz, 2H), 3.72-3.69 (br m, 2H), 3.62-3.60 (br m, 2H), 3.44-3.42 (brm, 2H), 3.29-3.27 (br m, 2H), 2.35 (m, 1H), 1.14 (d, J=6.7 Hz, 6H).

Example 119

1-Benzo[1,3]dioxo1-5-ylmethyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.035 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) usingbenzo[1,3]dioxol-5-ylmethyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded2-benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₀ClN₃O₂, 381.12; found, m/z 382.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.39-7.32 (m, 4H), 6.67-6.65 (m, 1H), 6.54-6.61 (m,2H), 5.81 (s, 2H), 5.16 (s, 2H), 2.81-2.79 (m, 4H), 2.76-2.74 (m, 2H),2.68-2.66 (m, 2H).

Example 120

3-(4-Chloro-phenyl)-1-(tetrahydro-pyran-4-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) usingtoluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (0.3 mmol) inplace of 2-chloromethyl-thiophene. The title compound was obtained as a2:1 mixture (25 mg) with3-(4-chloro-phenyl)-2-(tetrahydro-pyran-4-ylmethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.Data for the mixture: MS (ESI): exact mass calculated for C₁₉H₂₄ClN₃O,345.16; found, m/z 346.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.47-7.23 (m,4H), 4.10-3.78 (m, 4H), 3.37-3.14 (m, 8H), 3.06-2.67 (m, 2H), 2.02-1.93(m, 1H), 1.42-0.97 (m, 4H).

Example 121

3-(4-Chloro-phenyl)-1-(2,6-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.07 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 1 mmol) using2,6-difluorobenzyl chloride (1.5 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₁₈ClF₂N₃, 373.12; found, m/z 374.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H),3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).

Example 122

3-(4-Chloro-phenyl)-2-cyclohexylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.06 g) was prepared from3-(4-chloro-phenyl)-2-cyclohexylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 117) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated for C₂₀H₂₆ClN₃,343.18; found, m/z 344.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.39 (d, J=8.5Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.10 (d, J=7.3 Hz, 2H), 3.49-3.47 (brm, 2H), 3.37-3.35 (br m, 2H), 3.21-3.19 (br m, 2H), 3.03-3.01 (br m,2H), 1.88-1.61 (m, 4H), 1.52-1.49 (m, 2H), 1.17-1.10 (m, 3H), 0.94-0.90(m, 2H).

Example 123

3-(4-Chloro-phenyl)-1-(4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.1 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 1 mmol) using4-methoxybenzyl chloride (1.5 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₂₁H₂₂ClN₃O, 367.15; found, m/z 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):7.41-7.39 (m, 2H), 7.31 (d, J=7.7 Hz, 2H), 6.70 (d, J=7.7 Hz, 2H), 5.36(s, 2H), 3.60 (s, 3H), 3.33-3.31 (br m, 2H), 3.21-3.19 (br m, 2H),3.18-3.16 (br m, 2H), 2.96-2.94 (br m, 2H).

Example 124

3-(4-Chloro-phenyl)-1-(3-methyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.030 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using1-bromo-3-methyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₁₈H₂₄ClN₃, 317.17; found, m/z 318.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.56-7.54 (m, 4H), 4.34 (s, 2H),3.57-3.55 (br m, 2H), 3.44-3.42 (br m, 2H), 3.40-3.38 (br m, 2H),3.29-3.27 (br m, 2H), 1.79-1.77 (br m, 1H), 1.02 (d, J=4.5 Hz, 6H).

Example 125

3-(4-Chloro-phenyl)-1-(2-trifluoromethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.04 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2-trifluoromethylbenzyl bromide (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₁₉ClF₃N₃, 405.12; found, m/z 406.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 7.45 (d, J=7.7 Hz, 2H), 7.25-7.24 (br m, 3H),7.18-7.16 (br m, 3H), 6.46-6.44 (br m, 1H), 5.43-5.41 (s, 2H), 3.14-3.11(br m, 4H), 2.89-2.87 (br m, 4H).

Example 126

3-(4-Chloro-phenyl)-2-(2-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.020 g) was prepared from3-(4-chloro-phenyl)-2-(2-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 107) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated for C₂₁H₂₂ClN₃,351.15; found, m/z 352.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.47 (d, J=8.4Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.15 (m, 3H), 6.60 (d, J=7.6 Hz, 1H),5.23 (s, 2H), 3.46-3.44 (m, 2H), 3.36-3.34 (m, 2H), 3.21-3.19 (m , 2H),2.89-2.87 (m, 2H), 2.13 (s, 3H).

Example 127

2-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.018 g) was prepared from2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step D) according to the deprotectionmethod in Example 103, Step C. MS (ESI): exact mass calculated forC₂₀H₂₀ClN₃, 337.13; found, m/z 338.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.30-7.28 (m, 2H), 7.20-7.15 (m, 3H), 7.03-7.01 (m, 2H), 6.91-6.89 (m,2H), 5.06 (s, 2H), 3.03-3.01 (m, 2H), 2.94-2.90 (m, 4H), 2.51-2.49 (m,2H).

Example 128

3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

To a solution of3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.4 mmol) in toluene (3 mL)was added 4-methoxy-2-methyl-benzyl chloride (0.9 mmol) andcyanomethylene-tri-n-butylphosphorane (1 mmol). The mixture was heatedat 110° C. for 16 h. After concentration and purification (SiO₂,EtOAc/hexanes),3-(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester was obtained (54 mg). The other regioisomer,3-(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester, was also obtained (86 mg).3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (20 mg) was treated with TFA (1 mL) in CH₂Cl₂ (10mL) for 4 h. After concentration of the reaction mixture, the titlecompound was obtained (0.02 g). MS (ESI): exact mass calculated forC₂₂H₂₄ClN₃O, 381.16; found, m/z 382.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.39-7.37 (m, 2H), 7.34-7.32 (m, 2H), 6.68-6.66 (br m, 1H), 6.54-6.52(br m, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 2.81-2.79 (m, 4H),2.71-2.69 (m, 4H).

Example 129

3-(4-Chloro-phenyl)-2-(2,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.016 g) was prepared from3-(4-chloro-phenyl)-2-(2,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 108; 0.2 mmol) according to thedeprotection method in Example 103, Step C. MS (ESI): exact masscalculated for C₂₀H₁₈ClF₂N₃, 373.12; found, m/z 374.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 7.54 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H),6.96-6.88 (m, 3H), 5.27 (s, 2H), 3.46-3.44 (br m, 2H), 3.34-3.32 (br m,2H), 3.23-3.21 (br m, 2H), 2.86-2.84 (br m, 2H).

Example 130

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-furan-2-carboxylicacid ethyl ester

The title compound (0.008 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using5-chloro-furan-2-carboxylic acid ethyl ester (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also provided3-(4-chloro-phenyl)-1-(5-ethoxycarbonyl-furan-2-ylmethyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁H₂₂ClN₃O₃, 399.13; found, m/z 400.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.44 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.00(d, J=3.5 Hz, 1H), 6.21 (d, J=3.5 Hz, 1H), 5.09 (s, 2H), 4.21 (q, J=7.1Hz, 2H), 3.21-3.19 (m, 2H), 3.11-3.09 (m, 2H), 2.96-2.94 (m, 2H),2.61-2.59 (m, 2H), 1.24 (t, J=7.1 Hz, 2H).

Example 131

3-(4-Chloro-phenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.010 g) was prepared from3-(4-chloro-phenyl)-2-isobutyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 118, Step C) according to thedeprotection method from Example 103, Step C. MS (ESI): exact masscalculated for C₁₇H₂₂ClN₃, 303.15; found, m/z 304.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.58-7.56 (m, 2H), 7.37-7.34 (m, 2H), 3.81 (d, J=7.5 Hz,2H), 3.42-3.40 (m, 2H), 3.34-3.30 (m, 2H), 3.18-3.15 (m, 2H), 2.81-2.78(m, 2H), 2.02-2.00 (m, 1H), 0.74 (d, J=6.7 Hz, 6H).

Example 132

3-(4-Chloro-phenyl)-2-(2-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.040 g) was prepared from3-(4-chloro-phenyl)-2-(2-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 109) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₂₁H₂₂ClN₃O₃, 399.13; found, m/z 368.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.26 (d, J=6.5 Hz, 2H), 7.12 (t, J=7.6 Hz, 1H), 7.03 (d, J=6.5 Hz, 2H),6.80 (t, J=7.6 Hz, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.62 (d, J=7.6 Hz, 1H),5.08 (s, 2H), 2.99-2.97 (m, 2H), 2.89-2.87 (m, 4H), 2.49-2.47 (m, 2H).

Example 133

2-Benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

To a solution of2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (0.1 mmol) (Example 59, Step D) in THF (25 mL) wasadded lithium aluminum hydride (100 mg). The mixture was heated atreflux for 4 h. Water (1 mL) was added, the mixture was filtered, andthe filtrate was concentrated. After purification (SiO₂, EtOAc/hexanes),2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester was obtained. The intermediate was diluted withCH₂Cl₂ (5 mL) and TFA (1 mL) was added. The reaction mixture was stirredat RT for 4 h. The reaction mixture was concentrated to obtain the titlecompound (0.018 g). MS (ESI): exact mass calculated for C₂₀H₂₁N₃,303.17; found, m/z 304.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.38-7.35 (m,3H), 7.19-7.18 (m, 3H), 7.12-7.10 (m, 2H), 5.13 (s, 2H), 3.35-3.21 (brm, 6H), 3.34-3.30 (br m, 2H), 2.81-2.79 (br m, 2H).

Example 134

3-(4-Chloro-phenyl)-1-prop-2-ynyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.014 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-propynylchloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI):exact mass calculated for C₁₆H₁₆ClN₃, 285.10; found, m/z 286.2 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.38-7.32 (m, 4H), 7.13 (t, J=6.4 Hz, 1H), 5.48(d, J=6.4 Hz, 2H), 2.93-2.91 (m, 4H), 2.84-2.81 (m, 2H), 2.68-2.65 (m,2H).

Example 135

3-(4-Chloro-phenyl)-1-pentafluorophenylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.02 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) usingpentafluorophenylmethyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-pentafluorophenylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₁₅ClF₅N₃, 427.09; found, m/z 428.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.30 (br s, 4H), 5.34 (s, 2H), 3.01 (br s, 4H),2.90-2.88 (m, 2H), 2.71-2.69 (m, 2H).

Example 136

3-(4-Chloro-phenyl)-2-thiophen-2-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.010 g) was prepared from3-(4-chloro-phenyl)-2-thiophen-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester according to the method in Example 103. MS (ESI):exact mass calculated for C₁₈H₁₈ClN₃S, 343.09; found, m/z 344.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.60-7.58 (m, 2H), 7.38-7.35 (m, 2H), 7.32 (dd,J=5.1, 1.1 Hz, 1H), 6.92 (dd, J=5.1, 3.5 Hz, 1H), 6.78 (dd, J=3.5, 1.1Hz, 1H), 5.41 (s, 2H), 3.47-3.45 (m, 2H), 3.37-3.35 (m, 2H), 3.23-3.21(m, 2H), 2.85-2.83 (m, 2H).

Example 137

3-(4-Chloro-phenyl)-1-(2,4,6-trifluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.027 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2,4,6-trifluorobenzyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₂₀H₁₇ClF₃N₃, 391.11; found, m/z 392.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.30-7.26 (m, 4H), 6.80-6.78 (br m, 2H), 5.25 (s, 2H), 2.94-2.92 (m,4H), 2.82-2.80 (m, 2H), 2.66-2.62 (m, 2H).

Example 138

2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzonitrile

The title compound (0.032 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using2-chloro-benzonitrile (0.3 mmol) in place of 2-chloromethyl-thiophene.MS (ESI): exact mass calculated for C₂₁H₁₉ClN₄, 362.13; found, m/z 363.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.81 (d, J=7.6 Hz, 1H), 7.68-7.66 (brm, 1H), 7.54-7.51 (m, 3H), 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=7.6 Hz,1H), 5.64 (s, 2H), 3.51-3.49 (br m, 2H), 3.43-3.41 (br m, 2H), 3.31-3.29(br m, 2H), 3.13-3.11 (br m, 2H).

Example 139

3-(4-Chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.009 g) was prepared from3-(4-chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 115) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₁₈H₁₇Cl₂N₃S, 377.05; found, m/z 378.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.47-7.44 (m, 2H), 7.22-7.20 (m, 2H), 6.65 (d, J=3.8 Hz, 1H), 6.44 (d,J=3.8 Hz, 1H), 5.17 (s, 2H), 3.32-3.30 (m, 2H), 3.21-3.19 (m, 2H),3.07-3.05 (m, 2H), 2.70-2.68 (m, 2H).

Example 140

3-(4-Chloro-phenyl)-2-(2,6-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.036 g) was prepared from3-(4-chloro-phenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 121, Step C) according to thedeprotection method in Example 103, Step C. MS (ESI): exact masscalculated for C₂₀H₁₈ClF₂N₃, 373.12; found, m/z 374.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.44-7.42 (m, 2H), 7.27-7.23 (m, 3H), 6.79 (m, 2H),5.14 (s, 2H), 3.27-3.25 (m, 2H), 3.21-3.18 (m, 2H), 3.02-3.00 (m, 2H),2.69-2.67 (m, 2H).

Example 141

3-(4-Chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.021 g) was prepared from3-(4-chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 125) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₂₁H₁₉ClF₃N₃, 405.12; found, m/z 406.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):7.69 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.53-7.46 (m, 3H), 7.27(d, J=8.1, 2H), 6.83 (d, J=7.2 Hz, 1H), 5.47 (s, 2H), 3.51-3.49 (br m,2H), 3.42-3.40 (br m, 2H), 3.31-3.29 (br m, 2H), 2.94-2.92 (br m, 2H).

Example 142

3-(4-Chloro-phenyl)-1-naphthalen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.043 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) usingnaphthalen-2-ylmethyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₂₄H₂₂ClN₃, 387.15; found, m/z 388.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.74-7.69 (m, 3H), 7.45-7.38 (m, 5H), 7.34-7.32 (m, 1H), 7.18-7.16 (m,2H), 5.43 (s, 2H), 3.04 (m, 2H), 2.99-2.97 (m, 2H), 2.87-2.85 (m, 4H).

Example 143

3-(4-Chloro-phenyl)-2-(2-ethyl-butyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.012 g) was prepared from3-(4-chloro-phenyl)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 114) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated for C₁₉H₂₆ClN₃,331.18; found, m/z 332.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.50-7.25 (brm, 4H), 3.76-3.74 (m, 2H), 3.33-3.31 (br m, 2H), 3.22-3.20 (br m, 2H),3.09-3.07 (br m, 2H), 2.73-2.71 (br m, 2H), 1.56-1.54 (m, 1H), 1.16-1.14(m, 4H), 0.82-0.55 (m, 6H).

Example 144

5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-furan-2-carboxylicacid ethyl ester

The title compound (0.017 g) was prepared from3-(4-chloro-phenyl)-1-(5-ethoxycarbonyl-furan-2-ylmethyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 130) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₂₁H₂₂ClN₃O₃, 399.13; found, m/z 400.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.37-7.32 (m, 4H), 7.06 (d, J=3.5 Hz, 1H), 6.41 (d, J=3.5 Hz, 1H), 5.34(s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.26-3.24 (m, 2H), 3.19-3.17 (m, 2H),3.13-3.11 (m, 2H), 2.86-2.84 (m, 2H), 1.24 (t, J=7.1 Hz, 2H).

Example 145

3-(4-Chloro-phenyl)-1-naphthalen-1-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.015 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using1-naphthalen-methyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also provided3-(4-chloro-phenyl)-2-naphthalen-1-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₄H₂₂ClN₃, 387.15; found, m/z 388.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.79-7.18 (m, 11H), 5.74 (d, J=7.3 Hz, 2H), 3.42 (s, 2H),3.21-3.19 (br m, 2H), 3.10-3.08 (br m, 2H), 2.92-2.90 (br m, 2H),2.84-2.82 (br m, 2H).

Example 146

2-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.021 g) was prepared from2-benzo[1,3]dioxo1-5-ylmethyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 119) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₂₁H₂₀ClN₃O₂, 381.12; found, m/z 382.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.37-7.34 (m, 2H), 7.11-7.10 (m, 2H), 6.57 (d, J=7.9 Hz, 1H), 6.31-6.29(m, 2H), 5.79 (s, 2H), 4.95 (s, 2H), 3.55-3.40 (m, 1H), 2.82-2.80 (m,5H), 2.42-2.41 (m, 2H).

Example 147

[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-aceticacid methyl ester

The title compound (0.09 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 1 mmol) using 2-bromoaceticacid methyl ester (1.5 mmol) in place of 2-chloromethyl-thiophene. MS(ESI): exact mass calculated for C₁₆H₁₈ClN₃O₂, 319.11; found, m/z 320.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.31 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1Hz, 2H), 4.93 (s, 2H), 3.56 (s, 3H), 3.27-3.25 (br m, 2H), 3.19-3.17 (brm, 2H), 3.04-3.03 (br m, 2H), 2.90-2.88 (br m, 2H).

Example 148

2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-N-methyl-acetamide

To a solution of3-(4-chloro-phenyl)-1-methylcarbamoylmethyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (44 mg) (Example 147) in THF (0.5 mL) was added 8%aq. NaOH (0.3 mL). The mixture was stirred at RT for 16 h, and then wasacidified with 1 N HCl (0.5 mL). The mixture was extracted with CH₂Cl₂(2×2 mL). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated. The residue was diluted with CH₃CN (0.5 mL)and treated with DCC (26 mg) and HOBt (18 mg). After 2 h at RT, asolution of methylamine hydrochloride (70 mg) in H₂O (0.3 mL) was added.The mixture was stirred at RT for 16 h. Concentration of the reactionmixture and purification of the residue by SiO₂ chromatography(EtOAc/hexanes) gave3-(4-chloro-phenyl)-1-methylcarbamoylmethyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The intermediate was treated with TFA (1 mL) inCH₂Cl₂ (10 mL) for 4 h, and the solution was concentrated to obtain thetitle compound (0.015 g). MS (ESI): exact mass calculated forC₁₆H₁₉ClN₄O, 318.12; found, m/z 319.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.41-7.32 (m, 4H), 5.94 (br s, 1H), 4.70 (s, 2H), 2.98-2.90 (m, 4H),2.77-2.71 (m, 7H).

Example 149

3-(4-Chloro-phenyl)-2-pentafluorophenylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.016 g) was prepared from3-(4-chloro-phenyl)-2-pentafluorophenylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 135) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₂₀H₁₅ClF₅N₃, 427.09; found, m/z 428.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.45-7.43 (m, 2H), 7.26-7.23 (m, 2H), 5.15 (s, 2H), 2.91-2.89 (m, 2H),2.83-2.81 (m, 2H), 2.79-2.77 (m, 2H), 2.46-2.44(m, 2H).

Example 150

3-(4-Chloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.006 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using3,4,5-trimethoxybenzyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₃H₂₆ClN₃O₃, 427.17; found, m/z 428.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.51-7.49 (m, 2H), 7.46-7.44 (m, 2H), 6.44 (s, 2H),5.32 (s, 2H), 3.78 (s, 6H), 3.74 (s, 3H), 2.95-2.89 (m, 6H), 2.81-2.79(m, 2H).

Example 151

3-(4-Chloro-phenyl)-2-naphthalen-1-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.015 g) was prepared from3-(4-chloro-phenyl)-2-naphthalen-1-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 145) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated for C₂₄H₂₂ClN₃,387.15; found, m/z 388.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.78-7.75 (m,2H), 7.67 (d, J=8.3 Hz, 1H), 7.41-7.39 (m, 2H), 7.00 (td, J=8.0, 1.0 Hz,1H), 7.21-7.19 (m, 2H), 7.02-7.01 (m, 2H), 6.69-6.67 (dd, J=7.1, 1.0 Hz,1H), 5.56 (s, 2H), 3.31-3.29 (m, 2H), 2.90-2.88 (m, 4H), 2.49-2.47 (m,2H).

Example 152

3-(4-Chloro-phenyl)-1-(2,6-dimethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.018 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, step B; 0.2 mmol) using2,6-dimethylbenzyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₂₂H₂₄ClN₃, 365.17; found, m/z 366.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.48-7.45 (m, 4H), 7.17-7.15 (br m, 1H), 7.11-7.09 (m, 2H), 5.51 (s,2H), 3.43-3.41 (br m, 2H), 3.39-3.37 (br m, 2H), 3.31-3.29 (br m, 2H),3.10-3.08 (br m, 2H), 2.31 (s, 3H).

Example 153

3-(4-Chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (25 mg) was prepared from3-(4-chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 150) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₂₃H₂₆ClN₃O₃, 427.17; found, m/z 428.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.39-7.36 (m, 2H), 7.13-7.11 (m, 2H), 6.07 (s, 2H), 5.00 (s, 2H), 3.59(s, 9H), 2.90-2.70 (m, 6H), 2.46-2.44 (m, 2H).

Example 154

1-(3,4-Bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (22 mg) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.2 mmol) using3,4-bis(benzyloxy)benzyl chloride (0.3 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also provided2-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₃₄H₃₂ClN₃O₂, 549.22; found, m/z 550.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.36-7.16 (m, 14H), 6.86 (d, J=8.3 Hz, 1H), 6.65 (d,J=1.9 Hz, 1H), 6.56 (dd, J=8.3, 1.9 Hz, 1H), 5.13 (s, 2H), 4.99 (s, 2H),4.97 (s, 2H), 2.78-2.76 (m, 2H), 2.73-2.71 (m, 2H), 2.65 (m, 4H).

Example 155

2-(3,4-Bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (20 mg) was prepared from2-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 154) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated forC₃₄H₃₂ClN₃O₂, 549.22; found, m/z 550.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.43-7.30 (m, 12H), 7.07-7.05 (m, 2H), 6.89-6.87 (m, 1H), 6.47-6.46 (m,2H), 5.09 (s, 2H), 5.04 (s, 2H), 5.01 (s, 2H), 2.99-2.97 (m, 2H),2.93-2.91 (m, 2H), 2.88-2.86 (m, 2H), 2.52-2.50 (m, 2H).

Example 156

3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol

A solution of3-(4-chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 105, 0.1 mmol) in CH₂Cl₂ (5 mL) was cooled to 0° C., and 1 MBBr₃ in CH₂Cl₂ (0.5 mL) was added. The mixture was allowed to warm to25° C. After 2 h, satd. aq. NaHCO₃ (5 mL) was added. The layers wereseparated, and the aqueous layer was extracted with EtOAc (2×5 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated.Purification by flash chromatography (2 M NH₃ in MeOH/CH₂Cl₂) providedthe title compound (10 mg). MS (ESI): exact mass calculated forC₂₀H₂₀ClN₃O, 353.13; found, m/z 354.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.40-7.38 (m, 2H), 7.35-7.32 (m, 2H), 7.03 (t, J=7.9 Hz, 1H), 6.57 (dd,J=8.1, 2.0 Hz, 1H), 6.49 (d, J=8.1 Hz, 1H), 6.39-6.37 (br m, 1H), 5.20(s, 2H), 2.81-2.78 (br m, 4H), 2.74-2.72 (br m, 2H), 2.70-2.68 (br m,2H).

Example 157

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol

The title compound (10 mg) was prepared from(4-chloro-phenyl)-1-(4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 123, 0.1 mmol) as in Example 156. MS(ESI): exact mass calculated for C₂₀H₂₀ClN₃O, 353.13; found, m/z 354.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.39-7.37 (m, 2H), 7.34-7.31 (m, 2H),6.89-6.86 (m, 2H), 6.64-6.61 (m, 2H), 5.16 (s, 2H), 2.77-2.75 (br m,6H), 2.67-2.65 (br m, 2H).

Example 158

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-3-methyl-phenol

The title compound (8 mg) was prepared from(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 128, 34 mg) as in Example 156. MS (ESI):exact mass calculated for C₂₁H₂₂ClN₃O, 367.15; found, m/z 368.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.39-7.37 (m, 2H), 7.33-7.32 (m, 2H), 6.54-6.52(br m, 1H), 6.41-6.39 (br m, 1H), 6.28 (d, J=8.3 Hz, 1H), 5.17 (s, 2H),2.83-2.78 (m, 4H), 2.71-2.67 (m, 2H).

Example 159

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzene-1,2-diol

A solution of1-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-carboxylicacid tert-butyl ester (Example 154, 0.1 mmol) in CH₂Cl₂ (5 mL) wascooled to 0° C., and 1 M BBr₃ in CH₂Cl₂ (0.5 mL) was added. The mixturewas allowed to warm to RT and was stirred at RT for 1 h. The precipitatethat had formed was collected by filtration, washed with water, anddried under vacuum to provide the title compound (25 mg). MS (ESI):exact mass calculated for C₂₀H₂₀ClN₃O₂, 369.12; found, m/z 370.0 [M+H]⁺.1 H NMR (500 MHz, CD₃OD): 7.44-7.42 (m, 4H), 7.39-7.37 (m, 2H), 6.63 (d,J=8.1 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.45 (dd, J=8.1, 2.1 Hz, 1H),5.18 (s, 2H), 3.29-3.25 (m, 4H), 3.06-3.04 (m, 2H), 2.97-2.95 (m, 2H).

Example 160

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluoro-phenol

BBr₃ (0.13 mL) was added slowly to a 0° C. solution of 0.022 g of3-(4-chloro-phenyl)-1-(3-fluoro-4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 96) in CH₂Cl₂ (20 mL). After 1 h, the mixture was warmed to RTand stirred for 18 h. The reaction was then cooled back to 0° C. andquenched by the addition of 5 mL of satd. aq. NaHCO₃. The aqueous layerwas extracted with methanolic CH₂Cl₂ (2×). The combined organic layerswere dried over Na₂SO₄ and concentrated. The crude oil was purified bypreparative TLC (9:1 CH₂Cl₂/2 M NH₃ in MeOH) to afford the titlecompound (0.016 g) as a tan solid. MS (ESI): exact mass calculated forC₂₀H₁₉ClFN₃O, 371.12; found, m/z 372.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):7.50-7.42 (m, 4H), 6.86-6.79 (m, 3H), 5.26 (s, 2H), 3.31-3.26 (m, 2H),2.96-2.95 (m, 4H), 2.90-2.87 (m, 2H), 2.81-2.79 (m, 2H). ¹³C NMR (100MHz, CD₃OD): 154.2, 151.8, 149.6, 146.1, 146.0, 143.8, 134.8, 133.4,131.1, 130.3, 130.2, 129.7, 124.0, 119.1, 115.6, 115.4, 53.1, 50.4,29.0, 27.5.

Example 161

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-2-fluoro-phenol

3-(4-Chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 97, 0.12 g) was de-methylated as in Example 160 to afford thetitle compound (0.027 g) as an off-white solid. MS (ESI): exact masscalculated for C₂₀H₁₉ClFN₃O, 371.12; found, m/z 372.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.48-7.44 (m, 2H), 7.21-7.18 (m, 2H), 6.75 (t, J=8.6Hz, 1H), 6.61-6.58 (m, 1H), 6.53-6.50 (m 1H), 5.04 (s, 2H), 3.31-3.30(m, 2H), 3.01-2.99 (m, 2H), 2.94-2.88 (m, 4H), 2.55-2.52 (m, 2H). ¹³CNMR (125 MHz, CD₃OD): 154.2, 153.7, 152.3, 146.5, 146.4, 142.4, 136.6,133.1, 130.6, 130.5, 130.1, 124.5, 120.7, 119.2, 116.0, 115.9, 53.4,51.2, 32.6, 28.0.

Example 162

2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol

The title compound (13 mg) was prepared from3-(4-chloro-phenyl)-1-(2-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 109, 0.1 mmol) as in Example 156. MS(ESI): exact mass calculated for C₂₀H₂₀ClN₃O, 353.13; found, m/z 354.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.37 (d, J=6.5 Hz, 2H), 7.33 (d, J=6.5Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 6.62 (t, J=7.6 Hz, 1H), 5.12 (s, 2H), 2.91-2.80 (br m, 6H),2.68-2.66 (m, 2H).

Example 163

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-3-methyl-phenol

The title compound (14 mg) was prepared from(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 128, 42 mg) as in Example 156. MS (ESI):exact mass calculated for C₂₁H₂₂ClN₃O, 367.15; found, m/z 368.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.33-7.30 (m, 2H), 7.07-7.06 (m, 2H), 6.43 (d,J=2.3 Hz, 1H), 6.36 (dd, J=8.4, 2.3 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H),4.96 (s, 2H), 2.89-2.86 (m, 2H), 2.82-2.77 (m, 4H), 2.44 (m, 2H), 1.89(s, 3H).

Example 164

2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-phenol

The title compound (8 mg) was prepared from3-(4-chloro-phenyl)-2-(2-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 132, 30 mg) as in Example 156. MS (ESI):exact mass calculated for C₂₀H₂₀ClN₃O, 353.13; found, m/z 354.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.62 (d, J=6.5 Hz, 2H), 7.36-7.34 (m, 3H), 7.13(d, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.82 (t, J=8.0 Hz, 1H), 5.08(s, 2H), 3.11-3.00 (br m, 6H), 2.60-2.58 (m, 2H).

Example 165

1-Benzyl-3-(4-chloro-phenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

To a solution of1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 59, Step E; 0.1 mmol) in 1,2-dichloroethane (5 mL) was addedacetic acid (0.2 mmol), formaldehyde (37% water solution, 0.037 mL), andNaBH(OAc)₃ (0.2 mmol). The mixture was stirred at RT for 15 h. Themixture was diluted with CH₂Cl₂ and washed with satd. aq. NaHCO₃ (2×).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatography on SiO₂ (2 M NH₃ in MeOH/CH₂Cl₂)afforded 0.015 g of the title compound. MS (ESI): exact mass calculatedfor C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.19 (m, 3H),7.03-7.01 (br m, 2H), 5.27 (s, 2H), 2.75-2.68 (m, 4H), 2.64-2.58 (m,4H), 2.36 (s, 3H).

Examples 166 through 169 were synthesized using the procedure describedin Example 165 unless otherwise noted.

Example 166

1-Benzyl-3-(4-chloro-phenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (18 mg) was prepared using acetaldehyde (0.2 mmol) inplace of formaldehyde. MS (ESI): exact mass calculated for C₂₂H₂₄ClN₃,365.17; found, m/z 366.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.45-7.43 (m,2H), 7.31-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (br m, 2H), 5.26(s, 2H), 2.74-2.71 (m, 10H), 1.01 (t, J=7.1 Hz, 3H).

Example 167

3-(4-Chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

To a solution of3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 mmol) in CH₂Cl₂ (5 mL)was added TFA (1 mL). The mixture was stirred at RT for 16 h. Afterconcentration, the intermediate3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene wasobtained. The intermediate (0.1 mmol) was converted to the titlecompound (16 mg) according to the procedure described in Example 165using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS(ESI): exact mass calculated for C₂₂H₂₄ClN₃O₂, 397.16; found, m/z 398.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.38-7.35 (br m, 4H), 7.91 (d, J=1.8Hz, 1H), 6.82-6.80 (dd, J=8.1, 1.8 Hz, 1H), 6.76-6.74 (d, J=8.1 Hz, 1H),3.83-3.80 (s, 6H), 2.84-2.82 (m, 4H), 2.71-2.69 (m, 4H).

Example 168

1-Butyl-3-(4-chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (8 mg) was prepared from1-butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 67, 14 mg) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in placeof formaldehyde. MS (ESI): exact mass calculated for C₂₆H₃₂ClN₃O₂,453.22; found, m/z 454.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.38 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 6.91-6.90 (br m, 1H),6.81 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 3.98 (t, J=7.3 Hz, 2H),3.82 (d, J=7.0 Hz, 6H), 3.66 (s, 2H), 2.78-2.72 (br m, 8H), 1.67 (m,2H), 1.27 (m, 2H), 0.86 (t, J=7.3 Hz, 6H).

Example 169

1-Benzyl-3-(4-chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound was prepared (12 mg) from1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 59, Step E; 0.1 mmol) using 3,4-dimethoxy-benzaldehyde (0.2mmol) in place of formaldehyde. MS (ESI): exact mass calculated forC₂₉H₃₀ClN₃O₂, 487.20; found, m/z 488.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.44-7.43 (m, 2H), 7.30-7.29 (m, 2H), 7.25-7.22 (m, 2H), 7.20-7.18 (m,1H), 7.03-7.02 (m, 2H), 6.86 (d, J=1.7 Hz, 1H), 6.76-6.71 (m, 2H), 5.25(s, 2H), 3.79 (s, 6H), 3.63 (s, 2H), 2.72 (s, 4H), 2.68-2.66 (m, 4H).

Example 170

[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-aceticacid methyl ester

To a solution of1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 59, Step E; 1 mmol) in acetone (3 mL) was added Na₂CO₃ (2 mmol)and bromoacetic methyl ester (2 mmol). The mixture was stirred at RT for1 h. After concentration and purification (SiO₂, 2 M NH₃ inMeOH/CH₂Cl₂), the title compound was obtained (60 mg). MS (ESI): exactmass calculated for C₂₃H₂₄ClN₃O₂, 409.16; found, m/z 410.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.44-7.42 (m, 2H), 7.31-7.29 (m, 2H), 7.25-7.23(br m, 2H), 7.20-7.18 (br m, 1H), 7.02-6.99 (br m, 2H), 5.26 (s, 2H),3.64 (s, 2H), 3.41 (s, 2H), 2.81-2.79 (br m, 4H), 2.75-2.73 (br m, 2H),2.70-2.68 (br m, 2H).

Example 171

2-[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-ethanol

To a solution of[1-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-aceticacid methyl ester (Example 170, 16 mg) in THF (1 mL) was added lithiumaluminum hydride (100 mg). The mixture was stirred at RT for 16 h. Thereaction was quenched by the addition of H₂O (0.1 mL). Concentration andpurification (SiO₂, 2 M NH₃ in MeOH/CH₂Cl₂) provided the title compound(5 mg). MS (ESI): exact mass calculated for C₂₂H₂₄ClN₃O, 381.16; found,m/z 382.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.50-7.20 (m, 7H), 7.04 (d,J=7.2 Hz, 1H), 5.29 (s, 2H), 3.07-3.04 (m, 2H), 2.89-2.77 (m, 10H).

Example 172

3-(4-Chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

A solution of3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 59, Step C; 0.3 mmol) in CH₂Cl₂ (5 mL)was treated with phenylboronic acid (0.6 mmol), pyridine (0.6 mmol), andcopper(II) acetate (4.5 mmol). The mixture was stirred at RT for 16 h.After concentration and purification (SiO₂, EtOAc/hexanes),3-(4-chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester was obtained. This intermediate was then dilutedwith CH₂Cl₂ (10 mL), and TFA (1 mL) was added. The mixture was stirredat RT for 4 h. The mixture was concentrated and the residue was purified(SiO₂, 2 M NH₃ in MeOH/CH₂Cl₂) to provide the title compound (40 mg). MS(ESI): exact mass calculated for C₁₉H₁₈ClN₃, 323.12; found, m/z 324.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.46-7.40 (m, 4H), 7.36-7.32 (m, 5H),3.09-3.07 (br m, 4H), 3.00-2.98 (br m, 2H), 3.92-2.90 (br m, 2H).

Example 173

3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,6-triaza-cyclopentacyclooctene

Step A.3-(4-Chloro-phenyl)-1,4,5,7,8,9-hexahydro-1,2,6-triaza-cyclopentacyclooctene-6-carboxylicacid tert-butyl ester. To a 0° C. solution of 4-oxo-azepane-1-carboxylicacid tert-butyl ester (Example 59, Step B; 0.915 g) in Et₂O (30 mL) wasadded BF₃.Et₂O (0.733 mL) followed by a solution of1-(4-chlorophenyl)-2-diazo-ethanone (Example 103, Step A; 4.5 mmol) inEt₂O (30 mL). The mixture was warmed to 25° C. and stirred for 1 h.Satd. aq. NaHCO₃ (40 mL) was added, and the organic layer was separatedand concentrated. The resulting residue was diluted with MeOH (50 mL)and treated with hydrazine (1.5 mL). The reaction mixture was stirred at25° C. for 16 h. Concentration and purification by flash chromatography(SiO₂, EtOAc/CH₂Cl₂) provided the desired ester.

Step B.3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-1,4,5,7,8,9-hexahydro-1,2,6-triaza-cyclopentacyclooctene-6-carboxylicacid tert-butyl ester. A solution of the product from Step A (0.2 mmol)in DMF (2 mL) was treated with 2-methylbenzyl chloride (0.3 mmol)followed by Cs₂CO₃ (0.3 mmol). The mixture was stirred at 25° C. for 16h. Concentration and purification by chromatography (SiO₂,EtOAc/hexanes) provided the target intermediate.

Step C. A solution of the product from Step B in MeOH (20 mL) wastreated with HCl (2 M in Et₂O, 1 mL) for 16 h. After concentration andpurification by chromatography (SiO₂, 2 M NH₃ in MeOH/CH₂Cl₂), the titlecompound was obtained (24 mg). The reaction sequence also yielded3-(4-chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,7-triaza-cyclopentacyclooctene(20 mg). MS (ESI): exact mass calculated for C₂₂H₂₄ClN₃, 365.17; found,m/z 366.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.51-7.50 (m, 2H), 7.42-7.40(m, 2H), 7.14-7.05 (m, 3H), 6.58 (d, J=7.6 Hz, 1H), 5.42 (s, 2H), 3.25(t, J=5.6 Hz, 2H), 3.13 (t, J=5.6 Hz, 2H), 3.01 (t, J=5.6 Hz, 2H), 2.89(t, J=5.6 Hz, 2H), 2.30 (s, 3H), 1.78-1.76 (m, 2H).

Example 174

3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,7-triaza-cyclopentacyclooctene

The title compound (20 mg) was obtained as in Example 173. MS (ESI):exact mass calculated for C₂₂H₂₄ClN₃, 365.17; found, m/z 366.2 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.48-7.46 (m, 2H), 7.39-7.36 (m, 2H), 7.14-7.05(m, 3H), 6.55-6.54 (m, 1H), 5.39 (s, 2H), 3.02-3.00 (m, 2H), 2.98-2.96(m, 4H), 2.80-2.78 (m, 2H), 2.30-2.28 (s, 3H), 1.99-1.97 (m, 2H).

Example 175

3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

The title compound (22 mg) was prepared from3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.858 g) and1-(4-chlorophenyl)-2-diazo-ethanone (Example 103, Step A; 5.79 mmol) asin Example 173. MS (ESI): exact mass calculated for C₁₇H₂₂ClN₃O, 337.13;found, m/z 338.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.62-7.60 (m, 2H),7.36-7.34 (m, 2H), 7.14-7.06 (m, 3H), 6.76 (d, J=7.5 Hz, 1H), 5.33 (s,2H), 4.09 (s, 2H), 3.38 (t, J=6.1 Hz, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.25(s, 3H).

Example 176

2,3-Diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.3-Oxo-2-phenyl-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of the compound (3.13 g) fromExample 59, Step A in 80 mL of EtOH was added 1.2 mL of phenylhydrazine.The resulting solution was heated at reflux for 3 days and then wascooled to RT and the solvent was removed in vacuo. The residue waschromatographed on SiO₂ (0 to 80% EtOAc/hexanes) to afford 3.13 g of thedesired compound. MS (ESI): exact mass calculated for C₁₈H₂₃N₃O₃,329.17; found, m/z 330.2 [M+H]⁺.

Step B.2-Phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a stirred solution of the above compound (1.79g) in 35 mL of CH₂Cl₂ was added 3.0 mL of i-Pr₂NEt and 3.05 g ofN-phenyltrifluoromethanesulfonimide. The mixture was heated at refluxfor 24 h and then was concentrated in vacuo. Chromatography on SiO₂ (0to 75% EtOAc/hexanes) afforded 1.88 g of the desired compound. MS (ESI):exact mass calculated for C₁₉H₂₂F₃N₃O₅S, 461.12; found, m/z 407.1[M+H]⁺.

Step C.2,3-Diphenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of the above compound (0.28 g) in 5mL of 1,4-dioxane was added 0.29 g of K₃PO₄, 104.3 mg of phenylboronicacid and 43.0 mg of PdCl₂dppf. The mixture was heated at 80° C. for 3 h.More phenylboronic acid (0.10 g) and PdCl₂dppf (26 mg) were added andthe temperature was increased to 100° C. After an additional 12 h, themixture was poured into water (100 mL) and extracted with CH₂Cl₂ (3×20mL). The combined organic layers were filtered through diatomaceousearth and the filtrate was concentrated in vacuo. Chromatography on SiO₂(0 to 20% EtOAc/hexanes) afforded 158.8 mg of the desired compound. MS(ESI): exact mass calculated for C₂₄H₂₇N₃O₂, 389.21; found, m/z 390.2[M+H]⁺.

Step D. To a stirred solution of the above compound (158.8 mg) in 5 mLof EtOH was added 2 mL of 1.0 M HCl in Et₂O. The mixture was stirred atRT for 12 h and concentrated in vacuo to give 75.6 mg of the titlecompound. MS (ESI): exact mass calculated for C₁₉H₁₉N₃, 289.16; found,m/z 290.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.41-7.38 (m, 3H), 7.36-7.32(m, 3H), 7.23-7.18 (m, 4H), 3.49-3.45 (m, 2H), 3.38-3.34 (m, 2H),3.26-3.23 (m, 2H), 2.96-2.93 (m, 2H).

Example 177

2-Cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. Cyclohexyl-hydrazine hydrochloride. To a solution ofcyclohexanone (1.25 mL) in hexanes (8 mL) was added 1.59 g of tert-butylcarbazate. The mixture was heated at reflux for 10 min and then allowedto cool to RT. The white precipitate that had formed was removed byfiltration and washed with cold hexanes. The white solid was thentreated with BH₃ (1.0 M in THF, 12 mL). After stirring at RT for 20 min,the mixture was treated with 16 mL of 6 N HCl. The mixture was heated at110° C. for 20 min and then was concentrated in vacuo. The residue wastreated with 30 mL of THF. The title compound (1.82 g), a white solid,was collected from this mixture by filtration. MS (ESI): exact masscalculated for C₆H₁₄N₂, 114.12; found, m/z 115.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 3.05-2.99 (m, 1H), 2.11-2.09 (m, 2H), 1.88-1.86 (m, 2H),1.72-1.69 (m, 1H), 1.37-1.19 (m, 5H).

Step B.2-Cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired compound was made as in Steps A and Bof Example 176, with cyclohexylhydrazine hydrochloride from Step A inplace of phenylhydrazine. The hydrazine salt was neutralized with Dowex®550 resin prior to use.

Step C.2-Cyclohexyl-3-phenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of 126 mg of the compound from StepA in 3 mL of 1,4-dioxane were added 229 mg of K₃PO₄, 131 mg ofphenylboronic acid, and 7.5 mg of dppf. PdCl₂dppf (22 mg) was then addedand the mixture was heated at reflux overnight. The mixture wasconcentrated in vacuo and the residue was dissolved in toluene. Thesolution was filtered through diatomaceous earth and the filtrate wasconcentrated to afford 202 mg of an oil. Chromatography on SiO₂ (5 to25% EtOAc/hexanes) provided 98.7 mg of the desired compound. MS (ESI):exact mass calculated for C₂₄H₃₃N₃O₂, 395.26; found, m/z 396.2 [M+H]⁺.

Step D. The above compound (98.7 mg) was converted to the title compound(71.0 mg) as in Example 43, Step E, and the crude product waschromatographed on SiO₂ (2 to 8% 2 M NH₃ in MeOH/EtOAc). MS (ESI): exactmass calculated for C₁₉H₂₅N₃, 295.20; found, m/z 296.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.59-7.49 (m, 3H), 7.35-7.29 (m, 2H), 3.97-3.88 (m,1H), 3.44-3.38 (m, 2H), 3.34-3.27 (m, 2H), 3.20-3.14 (m, 2H), 2.81-2.73(m, 2H), 1.99-1.76 (m, 6H), 1.65 (br s, 1H), 1.28-1.17 (m, 3H).

Example 178

3-(4-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (48 mg) was prepared as in Example 177, Steps C andD, using 129 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 173 mg of4-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₄ClN₃, 329.17; found, m/z 330.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.60-7.53 (m, 2H), 7.36-7.27 (m, 2H), 3.94-3.83 (m, 1H), 3.43-3.36 (m,2H), 3.34-3.26 (m, 2H), 3.2-3.12 (m, 2H), 2.80-2.72 (m, 2H), 1.98-1.76(m, 6H), 1.67 (br s, 1H), 1.32-1.17 (m, 3H).

Example 179

2-Cyclohexyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-zulene

The title compound (68 mg) was prepared as in Example 177, Steps C andD, using 130 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 132 mg of4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₄F₃N₃, 363.19; found, m/z 364.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.90-7.84 (m, 2H), 7.57-7.50 (m, 2H), 4.64 (br s, 2H), 3.94-3.85 (m,1H), 3.33-3.05 (m, 4H), 2.93-2.72 (m, 2H), 2.00-1.76 (m, 6H), 1.67 (brs, 1H), 1.38-1.17 (m, 3H).

Example 180

2-Cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using cyclopentylhydrazine hydrochloride (madeaccording to the procedure of Example 177, Step A using cyclopentanonein place of cyclohexanone) in place of phenylhydrazine, t-butanol inplace of EtOH, with the addition of 3 equiv. of triethylamine.

Step B. The title compound (52 mg) was prepared from the product of StepA (101 mg) according to the procedure of Example 177, Steps C and D,using 109 mg of phenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₃N₃, 281.19; found, m/z 282.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.58-7.48 (m, 3H), 7.36-7.30 (m, 2H), 4.50 (m, 1H), 3.44-3.38 (m, 2H),3.34-3.27 (m, 2H), 3.22-3.16 (m, 2H), 2.81-2.75 (m, 2H), 2.06-1.84 (m,6H), 1.65-1.54 (m, 2H).

Example 181

3-(4-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (74 mg) was prepared as in Example 177, Steps C andD, using 215 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 296 mg of4-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₂ClN₃, 315.15; found, m/z 316.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.59-7.53 (m, 2H), 7.36-7.30 (m, 2H), 4.48 (m, 1H), 3.44-3.37 (m, 2H),3.34-3.27 (m, 2H), 3.22-3.15 (m, 2H), 2.81-2.74 (m, 2H), 2.06-1.84 (m,6H), 1.65-155 (m, 2H).

Example 182

2-Cyclopentyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (113 mg) was prepared as in Example 177, Steps C andD, using 200 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 185 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₂FN₃, 299.18; found, m/z 300.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.45-7.39 (m, 2H), 7.35-7.29 (m, 2H), 4.53 (m, 1H), 3.48-3.42 (m, 2H),3.36-3.28 (m, 2H), 3.28-3.23 (m, 2H), 2.84-2.78 (m, 2H), 2.08-1.85 (m,6H), 1.67-1.56 (m, 2H).

Example 183

2-(1-Ethyl-propyl)-3-(3-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-(1-Ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using (1-ethyl-propyl)-hydrazine hydrochloride(made from 3-pentanone as described in Example 177, Step A) in place ofphenylhydrazine. The hydrazine was neutralized with NaH in DMF prior touse.

Step B. The title compound (82 mg) was prepared as in Example 177, StepsC and D, using 150 mg of the triflate from Step A and 138 mg of3-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₄FN₃, 301.20; found, m/z 302.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.61-7.55 (m, 1H), 7.31-7.25 (m, 1H), 7.16-7.12 (m, 1H), 7.10-7.05 (m,1H), 3.85-3.77 (m, 1H), 3.45-3.40 (m, 2H), 3.35-3.29 (m, 2H), 3.23-3.18(m, 2H), 2.82-2.76 (m, 2H), 1.97-1.80 (m, 2H), 1.79-1.70 (m, 2H), 0.71(t, J=7.4 Hz, 3H).

Example 184

2-(1-Ethyl-propyl)-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (93 mg) was prepared as in Example 177, Steps C andD, using 150 mg of2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 183, Step A) and 138 mg of3-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₄FN₃, 301.20; found, m/z 302.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.44-7.30 (m, 4H), 3.92-3.85 (m, 1H), 3.51-3.43 (m, 2H), 3.38-3.33 (m,2H), 3.30-3.24 (m, 2H), 2.86-2.78 (m, 2H), 1.98-1.85 (m, 2H), 1.84-1.73(m, 2H), 0.73 (t, J=7.4 Hz, 3H).

Example 185

2-(1-Ethyl-propyl)-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (95 mg) was prepared as in Example 177, Steps C andD, using 150 mg of2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 183, Step A) and 126 mg of3-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₆H₂₃N₃S,289.16; found, m/z 290.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.68-7.64 (m,1H), 7.52-7.48 (m, 1H), 7.12-7.07 (m, 1H), 3.93-3.86 (m, 1H), 3.44-3.39(m, 2H), 3.34-3.28 (m, 2H), 3.22-3.17 (m, 2H), 2.85-2.79 (m, 2H),1.95-1.84 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).

Example 186

2-(1-Ethyl-propyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (40 mg) was prepared as in Example 177, Steps C andD, using 150 mg of2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 183, Step A) and 120 mg of phenylboronicacid. MS (ESI): exact mass calculated for C₁₈H₂₅N₃, 283.20; found, m/z284.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.48-7.38 (m, 3H), 7.24-7.19 (m,2H), 3.77-3.70 (m, 1H), 3.36-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.14-3.09(m, 2H), 2.71-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.68-1.58 (m, 2H), 0.61(t, J=7.4 Hz, 3H).

Example 187

3-(4-Chloro-phenyl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-(2,2,2-Trifluoro-ethyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using 2,2,2-trifluoroethylhydrazine in place ofphenylhydrazine.

Step B. The title compound (40 mg) was prepared as in Example 177, StepsC and D, using 304 mg of the triflate from Step A and 407 mg of4-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₅H₁₅ClF₃N₃, 329.09; found, m/z 330.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.62-7.52 (m, 2H), 7.40-7.29 (m, 2H), 4.70 (q, J=8.6 Hz, 2H), 3.44-3.37(m, 2H), 3.36-3.25 (m, 2H), 3.22-3.13 (m, 2H), 2.83-2.73 (m, 2H).

Example 188

2-(2,2,2-Trifluoro-ethyl)-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (128 mg) was prepared as in Example 177, Steps C andD, using 288 mg of2-(2,2,2-trifluoro-ethyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 187, Step A) and 468 mg of4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₁₅F₆N₃, 363.12; found, m/z 364.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.93-7.83 (m, 2H), 7.62-7.54 (m, 2H), 4.75 (q, J=8.6 Hz, 2H), 3.47-3.39(m, 2H), 3.38-3.27 (m, 2H), 3.24-3.15 (m, 2H), 2.87-2.76 (m, 2H).

Example 189

2-Isopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using isopropylhydrazine hydrochloride in place ofphenylhydrazine, t-butanol in place of EtOH, with the addition of 3equiv. of triethylamine.

Step B. The title compound (93 mg) was prepared as in Example 177, StepsC and D, using 172 mg of the triflate from Step A and 147 mg ofphenylboronic acid. MS (ESI): exact mass calculated for C₁₆H₂₁ N₃,255.17; found, m/z 256.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.58-7.49 (m,3H), 7.36-7.30 (m, 2H), 4.40 (m, 1H), 3.45-3.40 (m, 2H), 3.34-3.28 (m,2H), 3.23-3.18 (m, 2H), 2.82-2.75 (m, 2H), 1.40 (d, J=6.9 Hz, 6H).

Example 190

3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (92 mg) was prepared as in Example 177, Steps C andD, using 159 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 156 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₂₀FN₃, 273.16; found, m/z 274.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.42-7.35 (m, 2H), 7.33-7.27 (m, 2H), 4.37 (m, 1H), 3.46-3.39 (m, 2H),3.34-3.28 (m, 2H), 3.23-3.18 (m, 2H), 2.81-2.74 (m, 2H), 1.41 (d, J=6.9Hz, 6H).

Example 191

2-(1-Ethyl-propyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (35 mg) was prepared as in Example 177, Steps C andD, using 148 mg of2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 183, Step A) and 122 mg of2-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₆H₂₃N₃S,289.16; found, m/z 290.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.72-7.67 (m,1H), 7.25-7.21 (m, 1H), 7.13-7.09 (m, 1H), 4.01-3.94 (m, 1H), 3.43-3.38(m, 2H), 3.34-3.28 (m, 2H), 3.20-3.14 (m, 2H), 2.86-2.80 (m, 2H),1.95-1.85 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).

Example 192

2-Cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (114 mg) was prepared as in Example 177, Steps C andD, using 200 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 169 mg of3-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₆H₂₁N₃S,287.15; found, m/z 288.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.68-7.63 (m,1H), 7.56-7.51 (m, 1H), 7.17-7.12 (m, 1H), 4.58 (m, 1H), 3.43-3.37 (m,2H), 3.34-3.28 (m, 2H), 3.19-3.14 (m, 2H), 2.86-2.80 (m, 2H), 2.04-1.85(m, 6H), 1.67-1.57 (m, 2H).

Example 193

2-Ethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using ethylhydrazine oxalate in place ofphenylhydrazine, t-butanol in place of EtOH, with the addition of 3equiv. of triethylamine.

Step B. The title compound (106 mg) was prepared as in Example 177,Steps C and D, using 198 mg of the triflate from Step A and 122 mg ofphenylboronic acid. MS (ESI): exact mass calculated for C₁₅H₁₉N₃,241.16; found, m/z 242.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.61-7.54 (m,3H), 7.43-7.39 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.49-3.44 (m, 2H),3.37-3.32 (m, 2H), 3.28-3.22 (m, 2H), 2.89-2.82 (m, 2H), 1.33 (t, J=7.1Hz, 3H).

Example 194

2-Ethyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (114 mg) was prepared as in Example 177, Steps C andD, using 208 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 211 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₅H₁₈FN₃, 259.15; found, m/z 260.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.41-7.35 (m, 2H), 7.32-7.26 (m, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.43-3.38(m, 2H), 3.33-3.28 (m, 2H), 3.18-3.12 (m, 2H), 2.80-2.75 (m, 2H), 1.27(t, J=7.1 Hz, 3H).

Example 195

2-Ethyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (101 mg) was prepared as in Example 177, Steps C andD, using 148 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 306 mg of2-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₃H₁₇N₃S,247.11; found, m/z 248.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.62-7.57 (m,1H), 7.16-7.11 (m, 1H), 7.10-7.05 (m, 1H), 3.98 (q, J=7.1 Hz, 2H),3.33-3.27 (m, 2H), 3.24-3.18 (m, 2H), 3.07-3.01 (m, 2H), 2.80-2.73 (m,2H), 1.22 (t, J=7.1 Hz, 3H).

Example 196

2-(3-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-(3-Chloro-phenyl)-3-phenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired compound (53.9 mg) was prepared from142.7 mg of2-(3-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (made as in Example 176, Steps A and B) replacingphenylhydrazine with (3-chloro-phenyl)-hydrazine, as described inExample 43, Step D, using 102.1 mg of phenylboronic acid. MS (ESI):exact mass calculated for C₂₄H₂₆ClN₃O₂, 423.17; found, m/z 424.1 [M+H]⁺.

Step B. The above compound (53.9 mg) was converted to the title compound(37.6 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₁₉H₁₈ClN₃, 323.12; found, m/z 324.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.38-7.32 (m, 4H), 7.16-7.09 (m, 4H), 6.96-6.93 (m, 1H), 3.09-3.05 (m,2H), 3.02-2.98 (m, 2H), 2.97-2.94 (m, 2H), 2.65-2.62 (m, 2H), 2.07 (brs, 1H).

Example 197

2-(3-Fluoro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (37.6 mg) was prepared from 339.2 mg of2-(3-fluoro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (made as in Example 176, Steps A and B from(3-fluoro-phenyl)-hydrazine) as described in Example 196, using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₁₉H₁₈FN₃, 307.15; found, m/z 308.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.39-7.35 (m, 3H), 7.20-7.14 (m, 3H), 7.00-6.96 (m, 1H), 6.94-6.86 (m,2H), 3.13-3.09 (m, 2H), 3.06-3.02 (m, 2H), 3.01-2.96 (m, 2H), 2.69-2.66(m, 2H).

Example 198

2-(2-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (17.2 mg) was prepared from 199.8 mg of2-(2-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (made from (2-chloro-phenyl)-hydrazine as inExample 176, Steps A and B), as described in Example 196 using1,4-dioxane as the solvent. MS (ESI): exact mass calculated forC₁₉H₁₈ClN₃, 323.12; found, m/z 324.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.37-7.34 (m, 2H), 7.29-7.24 (m, 5H), 7.14-7.10 (m, 2H), 3.12-3.09 (m,2H), 3.04-2.99 (m, 4H), 2.74-2.71 (m, 2H), 2.13 (br s, 1H).

Example 199

2-Phenyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Phenyl-3-thiophen-2-yl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of 199.8 mg of2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 176, Step B) in 3.5 mL of DMF were added0.6 mL of 2 M aq. Na₂CO₃ and 75.6 mg of thiophene-2-boronic acid.PdCl₂dppf (20.2 mg) was added and the mixture was heated at 80° C. for16 h. The mixture was poured into water (50 mL) and extracted withCH₂Cl₂ (3×15 mL) and the combined organic layers were concentrated invacuo. Chromatography on SiO₂ (0 to 50% EtOAc/hexanes) afforded 58.9 mgof the desired compound as a white solid. MS (ESI): exact masscalculated for C₂₂H₂₅N₃O₂S, 395.17; found, m/z 396.1 [M+H]⁺.

Step B. The above compound (58.9 mg) was converted to the title compound(28.1 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₁₇H₁₇N₃S, 295.11; found, m/z 296.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.36 (dd, J=5.2, 1.3 Hz, 1H), 7.32-7.23 (m, 5H), 7.01 (dd, J=5.2, 3.3Hz, 1H), 6.85 (dd, J=3.3, 1.3 Hz, 1H), 3.11-3.08 (m, 2H), 3.03-2.99 (m,4H), 2.76-2.73 (m, 2H), 2.12 (br s, 1H).

Example 200

3-(4-Fluoro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (70.0 mg) was prepared from 207.0 mg of2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 176, Step B) and 98.5 mg of4-fluorophenylboronic acid as in Example 199. MS (ESI): exact masscalculated for C₁₉H₁₅FN₃, 307.15; found, m/z 308.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.28-7.24 (m, 2H), 7.22-7.16 (m, 3H), 7.13-7.10 (m, 2H),7.05-7.01 (m, 2H), 3.12-3.08 (m, 2H), 3.05-3.02 (m, 2H), 3.01-2.98 (m,2H), 2.68-2.64 (m, 2H).

Example 201

3-(4-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (9.3 mg) was prepared from 164.0 mg of2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 176, Step B) and 63.8 mg of4-chlorophenylboronic acid as in Example 196. MS (ESI): exact masscalculated for C₁₉H₁₈ClN₃, 323.12; found, m/z 324.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.33-7.25 (m, 4H), 7.23-7.16 (m, 3H), 7.09-7.06 (m, 2H),3.10-3.07 (m, 2H), 3.03-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.66-2.63 (m,2H).

Example 202

3-(3-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (37.5 mg) was prepared from 192.3 mg of2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 176, Step B) and 84.7 mg of3-chlorophenylboronic acid as in Example 199. MS (ESI): exact masscalculated for C₁₉H₁₈ClN₃, 323.12; found, m/z 324.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.32-7.16 (m, 8H), 7.01-6.98 (m, 1H), 3.12-3.08 (m, 2H),3.05-3.02 (m, 2H), 3.01-2.98 (m, 2H), 2.69-2.66 (m, 2H).

Example 203

2-Phenyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (17.5 mg) was prepared from 188.9 mg of2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 176, Step B) and 93.3 mg ofp-tolylboronic acid as in Example 199, using DME as the solvent. MS(ESI): exact mass calculated for C₂₀H₂₁N₃, 303.17; found, m/z 304.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.26-7.23 (m, 2H), 7.21-7.16 (m, 3H),7.15-7.12 (m, 2H), 7.04-7.01 (m, 2H), 3.11-3.07 (m, 2H), 3.04-3.00 (m,2H), 2.98-2.96 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H).

Example 204

2,3-Diphenyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step A.2,3-Diphenyl-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. To a solution of 156.6 mg of2-phenyl-3-trifluoromethanesulfonyloxy-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (made from 4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester as in Example 176, Steps A and B) inTHF/H₂O (10:1, 4 mL) were added 148.4 mg of K₂CO₃ and 56.2 mg ofphenylboronic acid. PdCl₂dppf (23.4 mg) was added and the mixture washeated at reflux for 16 h. The mixture was concentrated in vacuo. Theresidue was chromatographed on SiO₂ (0 to 75% EtOAc/hexanes) to afford45.6 mg of the desired ester as an off-white solid. MS (ESI): exact masscalculated for C₂₃H₂₅N₃O₂, 375.19; found, m/z 376.2 [M+H]⁺.

Step B. The above compound (45.6 mg) was converted to the title compound(24.5 mg) as in Example 26, Step B. MS (ESI): exact mass calculated forC₁₈H₂₅N₃, 275.14; found, m/z 276.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.34-7.22 (m, 8H), 7.16-7.12 (m, 2H), 3.96 (s, 2H), 3.23 (t, J=6.0 Hz,2H), 2.88 (t, J=6.0 Hz, 2H).

Example 205

3-Phenyl-2-(3-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.3-Phenyl-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired compound (172.0 mg) was prepared from279.1 of mg of3-trifluoromethanesulfonyloxy-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (made from (3-trifluoromethyl-phenyl)-hydrazine asin Example 176, Steps A and B) and 0.21 g of phenylboronic acid, asdescribed in Example 177, Step C. MS (ESI): exact mass calculated forC₂₅H₂₆F₃N₃O₂, 457.20; found, m/z 458.1 [M+H]⁺.

Step B. The above compound (172.0 mg) was converted to the titlecompound (106.4 mg) as in Example 26, Step B. MS (ESI): exact masscalculated for C₂₀H₁₈F₃N₃, 357.15; found, m/z 358.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.53 (s, 1H), 7.44-7.41 (m, 1H), 7.39-7.29 (m, 5H),7.17-7.13 (m, 2H), 3.12-3.09 (m, 2H), 3.06-3.02 (m, 2H), 3.00-2.97 (m,2H), 2.69-2.66 (m, 2H).

Example 206

3-(4-Methoxy-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (43.6 mg) was prepared from 198.3 mg of2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 176, Step B) and 94.7 mg of4-methoxyphenylboronic acid as described in Example 199. MS (ESI): exactmass calculated for C₂₀H₂₁N₃O, 319.17; found, m/z 320.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.28-7.24 (m, 2H), 7.21-7.17 (m, 3H), 7.07 (d, J=8.8Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.11-3.08 (m, 2H),3.04-3.01 (m, 2H), 3.00-2.97 (m, 2H), 2.68-2.65 (m, 2H).

Example 207

2-(4-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (50.4 mg) was prepared from 201.1 mg of2-(4-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (made from (4-chloro-phenyl)-hydrazine as inExample 176, Steps A and B), and 65.1 mg of phenylboronic acid asdescribed in Example 204. MS (ESI): exact mass calculated forC₁₉H₁₈ClN₃, 323.12; found, m/z 324.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.39-7.34 (m, 3H), 7.22-7.19 (m, 2H), 7.15-7.11 (m, 4H), 3.11-3.07 (m,2H), 3.04-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.67-2.64 (m, 2H).

Example 208

6-Methyl-2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

To a solution of 33.5 mg of2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 176,Step D) in 5 mL of CH₂Cl₂ were added 0.15 g of paraformaldehyde and 0.15g of NaBH(OAc)₃. The mixture was stirred at RT for 12 h and was dilutedwith 20 mL of 1 M NaOH. After stirring for 3 h, the mixture wasextracted with CH₂Cl₂ (2×10 mL) and the combined organic layers wereconcentrated. Chromatography on SiO₂ (0 to 5% 2 M NH₃ in MeOH/CH₂Cl₂)gave 22.3 mg of the title compound as a white solid. MS (ESI): exactmass calculated for C₂₀H₂₁N₃, 303.17; found, m/z 304.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.35-7.30 (m, 3H), 7.27-7.21 (m, 2H), 7.20-7.16 (m,3H), 7.15-7.12 (m, 2H), 3.06-3.02 (m, 2H), 2.83-2.79 (m, 2H), 2.72-2.67(m, 4H), 2.50 (s, 3H).

Example 209

2-Isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (129 mg) was prepared as in Example 177, Steps C andD, using 204 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 194 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₃N₃, 269.19; found, m/z 270.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.28(d, J=7.7 Hz, 2H), 7.12 (d, J=7.7 Hz, 2H), 4.32 (m, 1H), 3.34-3.33 (m,2H), 3.12-3.10 (m, 2H), 2.70-2.68 (m, 2H), 2.33 (s, 3H), 1.30 (d, J=6.6Hz, 6H).

Example 210

3-(4-Ethyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (134 mg) was prepared as in Example 177, Steps C andD, using 202 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 212 mg of4-ethylphenylboronic acid. MS (ESI): exact mass calculated for C₁₈H₂₅N₃,283.20; found, m/z 284.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.44 (d, J=7.7Hz, 2H), 7.31 (d, J=7.7 Hz, 2H), 4.52 (m, 1H), 3.50-3.48 (m, 2H),3.36-3.34 (m, 2H), 2.85-2.83 (m, 2H), 2.75 (q, J=7.7 Hz, 2H), 1.47 (d,J=6.6 Hz, 6H), 1.29 (t, J=7.7 Hz, 3H).

Example 211

3-(4-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (82 mg) was prepared as in Example 177, Steps C andD, using 205 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 332 mg of2-(4-chloro-phenyl)benzo[1,3,2]dioxaborole. MS (ESI): exact masscalculated for C₁₆H₂₀ClN₃, 289.13; found, m/z 290.4 [M+H]⁺, 292.4[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5Hz, 2H), 4.36 (m, 1H), 3.44-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.81-2.76(m, 2H), 1.40 (d, J=6.6 Hz, 6H).

Example 212

4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

The title compound (95 mg) was prepared as in Example 177, Steps C andD, using 205 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 211 mg of4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C₁₇H₂₀N₄,280.17; found, m/z 281.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.57 (d, J=8.5Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.42-3.40 (m, 2H),3.19-3.17 (m, 2H), 2.79-2.77 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).

Example 213

2-Isopropyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (103 mg) was prepared as in Example 177, Steps C andD, using 199 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 265 mg of4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₀F₃N₃, 323.16; found, m/z 324.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.86 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 4.34 (m, 1H), 3.43-3.40(m, 2H), 3.20-3.18 (m, 2H), 2.80-2.78 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).

Example 214

2-Ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (136 mg) was prepared as in Example 177, Steps C andD, using 201 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 198 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₂₁N₃, 255.17; found, m/z 256.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.38(d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.67 (br s, 1H), 4.05 (q,J=7.1 Hz, 2H), 3.92-3.41 (m, 2H), 3.28-3.18 (m, 3H), 2.89-2.80 (m, 2H),2.43 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).

Example 215

2-tert-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-(tert-Butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using tert-butyl hydrazine hydrochloride in placeof phenylhydrazine, t-butanol in place of EtOH, with the addition of 3equiv. of triethylamine.

Step B. The title compound (53 mg) was prepared as in Example 177, StepsC and D, using 200 mg of the triflate from Step A and 166 mg ofphenylboronic acid. MS (ESI): exact mass calculated for C₁₇H₂₃N₃,269.19; found, m/z 270.5 [M+H]⁺, 214.4 [M−^(t)Bu]⁺. ¹H NMR (500 MHz,CD₃OD): 7.49-7.47 (m, 3H), 7.32-7.30 (m, 2H), 3.41-3.39 (m, 2H),3.25-3.23 (m, 2H), 3.18-3.15 (m, 2H), 2.52-2.520 (m, 2H), 1.41 (s, 9H).

Example 216

2-tert-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (88 mg) was prepared as in Example 177, Steps C andD, using 204 mg of2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 215 Step A) and 194 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₂FN₃, 287.18; found, m/z 288.4 [M+H]⁺, 232.4 [M−^(t)Bu]⁺. ¹H NMR(500 MHz, CD₃OD): 7.37-7.33 (m, 2H), 7.26-7.22 (m, 2H), 3.41-3.38 (m,2H), 3.26-3.24 (m, 2H), 3.18-3.15 (m, 2H), 2.53-2.51 (m, 2H), 1.42 (s,9H).

Example 217

2-Cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (70.4 mg) was prepared as in Example 177, Steps C andD, using 204.3 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 204.1 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₅N₃, 295.42; found, m/z 296.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.37(d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.50 (m, 1H), 3.43-3.40 (m,2H), 3.32-3.28 (m, 2H), 3.20-3.17 (m, 2H), 2.80-2.77 (m, 2H), 2.43 (s,3H), 2.04-1.86 (m, 6H), 1.64-1.55 (m, 2H).

Example 218

2-Cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (45.2 mg) was prepared as in Example 177, Steps C andD, using 269.2 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 359.2 mg of4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₂F₃N₃, 349.49; found, m/z 350.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.87 (d, J=7.9 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 4.48 (m, 1H), 3.43-3.40(m, 2H), 3.21-3.17 (m, 2H), 2.81-2.77 (m, 2H), 2.07-1.86 (m, 6H),1.66-1.57 (m, 2H).

Example 219

3-(3-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (34.9 mg) was prepared as in Example 177, Steps C andD, using 204.4 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 234.5 mg of3-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₂ClN₃, 315.84; found, m/z 316.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.57-7.52 (m, 2H), 7.37-7.35 (m, 1H), 7.29-7.26 (m, 1H), 4.46 (m, 1H),3.43-3.39 (m, 2H), 3.20-3.16 (m, 2H), 2.80-2.76 (m, 2H), 2.06-1.86 (m,6H), 1.66-1.57 (m, 2H).

Example 220

2-Cyclopentyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (34.9 mg) was prepared as in Example 177, Steps C andD, using 299.2 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 329.2 mg of4-methoxyphenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₅N₃O, 311.42; found, m/z 312.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.26-7.23 (m, 2H), 7.11-7.08 (m, 2H), 4.51 (m, 1H), 3.87 (s, 3H),3.43-3.40 (m, 2H), 3.20-3.16 (m, 2H), 2.80-2.76 (m, 2H), 2.02-1.86 (m,6H), 1.64-1.55 (m, 2H).

Example 221

2-(3,3-Dimethyl-cyclopentyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-(3,3-Dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using (3,3-dimethyl-cyclopentyl)-hydrazinehydrochloride in place of phenylhydrazine, t-butanol in place of EtOH,with the addition of 3 equiv. of triethylamine.

Step B. The title compound (92.8 mg) was prepared as in Example 177,Steps C and D, using 197.5 mg of the triflate from Step A and 150 mg ofphenylboronic acid. MS (ESI): exact mass calculated for C₂₀H₂₇N₃,309.45; found, m/z 310.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.58-7.50 (m,3H), 7.34-7.31 (m, 2H), 4.66-4.58 (m, 1H), 3.44-3.40 (m, 2H), 3.32-3.28(m, 2H), 3.21-3.17 (m, 2H), 2.81-2.77 (m, 2H), 2.21-2.03 (m, 2H),2.01-1.95 (m, 1H), 1.80-1.73 (m, 2H), 1.48-1.39 (m, 1H), 1.16 (s, 3H),0.92 (s, 3H).

Example 222

2-(3,3-Dimethyl-cyclopentyl)-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (52.6 mg) was prepared as in Example 177, Steps C andD, using 201.7 mg of2-(3,3-dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 221, Step A) and 180 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₆FN₃, 327.44; found, m/z 328.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.39-7.34 (m, 2H), 7.33-7.28 (m, 2H), 4.62-4.53 (m, 1H), 3.44-3.39 (m,2H), 3.31-3.29 (m, 2H), 3.21-3.17 (m, 2H), 2.80-2.75 (m, 2H), 2.20-2.03(m, 2H), 2.00-1.94 (m, 1H), 1.80-1.73 (m, 2H), 1.49-1.41 (m, 1H), 1.16(s, 3H), 0.93 (s, 3H).

Example 223

3-(4-Chloro-phenyl)-2-(3,3-dimethyl-cyclopentyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (25.6 mg) was prepared as in Example 177, Steps C andD, using 203.3 mg of2-(3,3-dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 221 Step A) and 204.1 mg of4-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₆ClN₃, 343.89; found, m/z 344.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.57 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 4.62-4.54 (m, 1H),3.43-3.39 (m, 2H), 3.32-3.28 (m, 2H), 3.20-3.16 (m, 2H), 2.79-2.75 (m,2H), 2.19-2.03 (m, 2H), 1.99-1.94 (m, 1H), 1.80-1.73 (m, 2H), 1.49-1.40(m, 1H), 1.16 (s, 3H), 0.94 (s, 3H).

Example 224

2-Cyclohexyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (17.2 mg) was prepared as in Example 177, Steps C andD, using 206.5 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 193.2 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₄FN₃, 313.41; found, m/z 314.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.37-7.28 (m, 4H), 3.91-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.32-3.27 (m,2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.79 (m, 6H), 1.69-1.63(m, 1H), 1.30-1.19 (m, 3H).

Example 225

2-Cyclohexyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (42.7 mg) was prepared as in Example 177, Steps C andD, using 205.2 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 224.9 mg of3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₃F₂N₃, 331.40; found, m/z 332.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.51-7.44 (m, 1H), 7.34-7.28 (m, 1H), 7.17-7.13 (m, 1H), 3.91-3.84 (m,1H), 3.42-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.78(m, 6H), 1.70-1.64 (m, 1H), 1.32-1.19 (m, 3H).

Example 226

2-Cyclohexyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (60.2 mg) was prepared as in Example 177, Steps C andD, using 203.8 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 181.6 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₇N₃, 309.45; found, m/z 310.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.37(d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.97-3.89 (m, 1H), 3.44-3.39(m, 2H), 3.31-3.26 (m, 2H), 3.20-3.15 (m, 2H), 2.80-2.75 (m, 2H),1.96-1.78 (m, 6H), 1.70-1.62 (m, 1H), 1.28-1.18 (m, 3H).

Example 227

2-Cyclohexyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (96.8 mg) was prepared as in Example 177, Steps C andD, using 207 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 224.1 mg of4-methoxyphenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₇N₃O, 325.45; found, m/z 326.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.25 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 4.00-3.92 (m, 1H), 3.87(s, 3H), 3.45-3.40 (m, 2H), 3.22-3.17 (m, 2H), 2.81-2.75 (m, 2H),1.96-1.65 (m, 7H), 1.29-1.19 (m, 3H).

Example 228

4-(2-Cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

The title compound (135.4 mg) was prepared as in Example 177, Steps Cand D, using 203.8 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 198 mg of4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C₂₀H₂₄N₄,320.43; found, m/z 321.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.93 (d, J=8.5Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 3.92-3.84 (m, 1H), 3.43-3.38 (m, 2H),3.19-3.15 (m, 2H), 2.80-2.75 (m, 2H), 1.98-1.80 (m, 6H), 1.71-1.64 (m,1H), 1.32-1.20 (m, 3H).

Example 229

3-(3-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (14.4 mg) was prepared as in Example 177, Steps C andD, using 199.3 mg of2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 177, Step B) and 216.2 mg of3-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₄ClN₃, 329.87; found, m/z 330.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.57-7.54 (m, 2H), 7.35 (s, 1H), 7.28-7.25 (m, 1H), 3.91-3.84 (m, 1H),3.43-3.38 (m, 2H), 3.19-3.14 (m, 2H), 2.79-2.74 (m, 2H), 1.97-1.80 (m,6H), 1.71-1.64 (m, 1H), 1.28-1.19 (m, 3H).

Example 230

{4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenyl}-methyl-amine

A mixture of1-(4-bromo-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 113; 0.04 mmol), tert-butyl carbamate(0.05 mmol), sodium phenoxide trihydrate (0.05 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.001 mmol), andtri-tert-butylphosphine (0.05 mmol) in anhydrous toluene (3 mL) washeated under N₂ at 100° C. for 6 h, 70° C. for 15 h and 100° C. for 2.5h. After cooling to RT, the reaction mixture was purified directly bypreparative TLC (2:1 hexanes/EtOAc) to yield 0.008 g of1-(4-tert-butoxycarbonylamino-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester, which was then diluted with DMF (1 mL) andtreated with NaH (60%, 1.5 equiv.). After 15 min, methyl iodide (1.5equiv.) was added. After 1 h, the reaction was quenched with H₂O and themixture was extracted with EtOAc (2×). The combined organic layers weredried over Na₂SO₄ and concentrated. The resulting semi-solid was thendissolved in CH₂Cl₂/MeOH (9:1, 1 mL) and treated with HCl (1 N in Et₂O,4 mL). The mixture was stirred at RT for 3 h, then was concentrated. Theresulting oil was purified by preparative TLC (10% 2 M NH₃ inMeOH/CH₂Cl₂) to yield 0.002 mg of the title compound as a white solid.MS (ESI): exact mass calculated for C₂₁H₂₃ClN₄, 366.16; found, m/z 367.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.39-7.32 (m, 4H), 6.84 (d, J=8.6 Hz,1H), 6.48-6.45 (m, 2H), 5.12 (s, 2H), 2.84-2.81 (m, 4H), 2.79-2.77 (m,2H), 2.69-2.66 (m, 2H), 2.63 (s, 3H).

Example 231

3-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step A.2-Isopropyl-3-trifluoromethanesulfonyloxy-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. The desired triflate was prepared according toExample 189, Step A, starting with 4-oxo-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester.

Step B. The title compound (26 mg) was prepared as in Example 177, StepsC and D, using 221 mg of the triflate from Step A and 140 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₅H₁₈FN₃, 259.32; found, m/z 260.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.44-7.39 (m, 2H), 7.33-7.28 (m, 2H), 4.48 (m, 1H), 4.15 (s, 2H), 3.58(t, J=6.3 Hz, 2H), 3.08 (t, J=6.3 Hz, 2H), 1.42 (d, J=6.6 Hz, 6H).

Example 232

2-Cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (101 mg) was prepared according to Example 180 using202 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 149 mg of 3-furanboronicacid. MS (ESI): exact mass calculated for C₁₆H₂₁N₃O, 271.17; found, m/z272.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.73-7.72 (m, 2H), 6.57-6.56 (m,1H), 4.64 (m, 1H), 3.40-3.38 (m, 2H), 3.16-3.14 (m, 2H), 2.86-2.84 (m,2H), 2.03-1.91 (m, 6H), 1.66-1.64 (m, 2H).

Example 233 28

2-Cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (83 mg) was prepared according to Example 180 using200 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 282 mg of2-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₆H₂₁N₃S,287.15; found, m/z 288.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.70-7.68 (m,1H), 7.24-7.22 (m, 1H), 7.15-7.14 (m, 1H), 4.64 (m, 1H), 3.41-3.39 (m,2H), 3.16-3.15 (m, 2H), 2.85-2.83 (m, 2H), 2.01-1.88 (m, 6H), 1.64-1.60(m, 2H).

Example 234

2-tert-Butyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (83 mg) was prepared according to Example 215 using204 mg of2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 215, Step A) and 177 mg of3-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₅H₂₁N₃S,275.15; found, m/z 276.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.59-7.57 (m,1H), 7.43-7.42 (m, 1H), 7.08-7.06 (m, 1H), 3.38-3.36 (m, 2H), 3.25-3.23(m, 2H), 3.13-3.11 (m, 2H), 2.56-2.54 (m, 2H), 1.43 (s, 9H).

Example 235

2-tert-Butyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (60 mg) was prepared according to Example 215 using203 mg of2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 215, Step A) and 154 mg of 3-furanboronicacid. MS (ESI): exact mass calculated for C₁₅H₂₁N₃O, 259.17; found, m/z260.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.69-7.68 (m, 1H), 7.61 (br s,1H), 6.50-6.49 (m, 1H), 3.38-3.36 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11(m, 2H), 2.63-2.61 (m, 2H), 1.50 (s, 9H).

Example 236

2-Cyclopentyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (70 mg) was prepared according to Example 180 using209 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 218 mg of3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₁F₂N₃, 317.17; found, m/z 318.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.50-7.45 (m, 1H), 7.36-7.32 (m, 1H), 7.18-7.17 (m, 1H), 4.49 (m, 1H),3.43-3.41 (m, 2H), 3.21-3.19 (m, 2H), 2.80-2.78 (m, 2H), 2.15-1.87 (m,6H), 1.66-1.61 (m, 2H).

Example 237

3-(4-Chloro-phenyl)-1-cyclobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.01 g) was prepared from3-(4-chloro-phenyl)-1-cyclobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 238) according to Example 103, Step C.(MS (ESI): exact mass calculated for C₁₇H₂₀ClN₃, 301.13; found, m/z302.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.54-7.48 (m, 4H), 5.15-5.05 (m,1H), 3.47-3.46 (m, 2H), 3.35-3.30 (m, 4H), 3.22-3.21 (m, 2H), 2.70-2.60(m, 2H), 2.50-2.40 (m, 2H), 1.90-1.80 (m, 2H).

Example 238

3-(4-Chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

To a solution of3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.40 mmol) in DMF (2 mL) wasadded NaH (60% dispersion in oil, 60 mg) at 25 ° C. After 10 min, themixture was heated to 80 ° C., and chloro-cyclobutane (1.5 mmol) wasadded. The mixture was heated at this temperature for 16 h. The mixturewas concentrated and purified by chromatography (SiO₂, EtOAc/hexanes) toprovide3-(4-chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The title compound (0.030 mg) was obtained fromthis ester according to the deprotection method in Example 103, Step C.The reaction sequence also yielded3-(4-chloro-phenyl)-1-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₇H₂₀ClN₃, 301.13; found, m/z 302.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.52-7.51 (m, 2H), 7.30-7.29 (m, 2H), 4.70-4.60 (m, 1H),3.40-3.89 (m, 2H), 3.27-3.21 (m, 4H), 2.79-2.76 (m, 2H), 2.60-2.50 (m,2H), 2.30-2.20 (m, 2H), 1.81-1.65 (m, 2H).

Example 239

3-(4-Chloro-phenyl)-1-cyclohexyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (15 mg) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.40 mmol) usingbromo-cyclohexane (1.5 mmol) in place of chloro-cyclobutane according toExample 238. MS (ESI): exact mass calculated for C₁₉H₂₄ClN₃, 329.17;found, m/z 330.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.45-7.41 (m, 4H),4.30-4.27 (m, 1H), 3.44-3.42 (m, 2H), 3.31-3.26 (m, 4H), 2.98-2.96 (m,2H), 1.93-1.84 (m, 5H), 1.70-1.65 (m, 1H), 1.46-1.40 (m, 2H), 1.24-1.89(m, 2H).

Example 240

2-tert-Butyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (83 mg) was prepared according to Example 215 using203 mg of2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 215, Step A) and 176 mg of2-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₅H₂₁N₃S,275.15; found, m/z 276.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.57-7.56 (m,1H), 7.08-7.06 (m, 1H), 7.01-7.00 (m, 1H), 3.29-3.27 (m, 2H), 3.17-3.14(m, 2H), 2.51-2.48 (m, 2H), 1.37 (s, 9H).

Example 241

3-(4-Chloro-3-fluoro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (31 mg) was prepared according to Example 180 using146 mg of2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 180, Step A) and 168 mg of3-chloro-4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₁ClFN₃, 333.14; found, m/z 334.4 [M+H]⁺, 336.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.39-7.31 (m, 2H), 7.22-7.18 (m, 1H), 4.37 (m, 1H),3.31-3.28 (m, 2H), 3.07-3.03 (m, 2H), 2.67-2.64 (m, 2H), 2.11-1.78 (m,6H), 1.56-1.47 (m, 2H).

Example 242

2-Isopropyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (148 mg) was prepared according to Example 189 using206 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 219 mg of4-methoxyphenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₃N₃O, 285.18; found, m/z 286.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.30-7.28 (m, 2H), 7.13-7.11 (m, 2H), 4.68 (m, 1H), 4.47 (m, 1H), 3.87(s, 3H), 3.47-3.44 (m, 1H), 3.25-3.23 (m, 1H), 2.89-2.81 (m, 2H), 1.43(d, J=6.6 Hz, 6H).

Example 243

2-Isopropyl-3-(4-trifluoromethoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (196 mg) was prepared according to Example 189 using278 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 402 mg of4-trifluoromethoxyphenylboronic acid. MS (ESI): exact mass calculatedfor C₁₇H₂₀F₃N₃O, 339.36; found, m/z 340.5 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): 7.53-7.45 (m, 4H), 4.66 (br s, 1H), 4.40 (J=6.68 Hz, 1H),3.45-3.43 (m, 1H), 3.23-3.21 (m, 1H), 2.88-2.79 (m, 2H), 1.42 (d, J=6.7Hz, 6H).

Example 244

2-Isopropyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (177 mg) was prepared according to Example 189 using270 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 311 mg of4-isopropylphenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₇N₃, 297.44; found, m/z 298.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.35-7.34 (m, 2H), 7.19-7.17 (m, 2H), 4.57 (br s, 1H), 4.38-4.32 (m,1H), 3.36-3.34 (m, 1H), 3.15-3.13 (m, 1H), 2.90 (m, 1H), 2.79-2.70 (m,2H), 1.31 (d, J=13.3 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H).

Example 245

3-(4-tert-Butyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (28 mg) was prepared according to Example 189 using215 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 268 mg of4-tert-butylphenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₉N₃, 311.24; found, m/z 312.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.61-7.59 (m, 2H), 7.27-7.25 (m, 2H), 4.40 (m, 1H), 3.43-3.40 (m, 2H),3.19-3.17 (m, 2H), 2.79-2.77 (m, 2H), 1.50-1.25 (m, 15H).

Example 246

2-Isopropyl-3-m-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (24 mg) was prepared according to Example 189 using219 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 209 mg of3-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₃N₃, 269.19; found, m/z 270.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.44-7.41 (m, 1H), 7.34-7.33 (m, 1H), 7.13-7.10 (m, 2H), 4.37 (m, 1H),3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.78-2.76 (m, 2H), 2.42 (s, 3H),1.38 (d, J=6.7 Hz, 6H).

Example 247

2-Isopropyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (80 mg) was prepared according to Example 189 using207 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 198 mg of2-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₃N₃, 269.19; found, m/z 270.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.45-7.40 (m, 2H), 7.36-7.33 (m, 1H), 7.19-7.18 (m, 1H), 4.66 (br s,2H), 4.10 (m, 1H), 4.00-3.66 (m, 2H), 2.76-2.61 (m, 2H), 2.13 (s, 3H),1.45-1.29 (m, 6H).

Example 248

3-(3,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (60 mg) was prepared according to Example 189 using200 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 268 mg of3,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₁₉Cl₂N₃, 323.10; found, m/z 324.4 [M+H]⁺, 326.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.72-7.71 (m, 1H), 7.53-7.52 (m, 1H), 7.29-7.27 (m, 1H),4.64 (br s, 2H), 4.32 (m, 1H), 3.86-3.57 (m, 2H), 3.31-3.08 (m, 2H),2.84-2.75 (m, 2H), 1.39 (d, J=6.6 Hz, 6H).

Example 249

2-Benzyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared according toExample 189, Step A, using benzylhydrazine hydrochloride in place ofisopropylhydrazine hydrochloride.

Step B. The title compound (29 mg) was prepared as in Example 177, StepsC and D, using 230 mg of the triflate from Step A and 234 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₂₀H₂₀FN₃, 321.39; found, m/z 322.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.31-7.19 (m, 7H), 6.97-6.93 (m, 2H), 5.20 (s, 2H), 3.45-3.40 (m, 2H),3.35-3.30, (m, 2H), 3.20-3.15 (m, 2H), 2.83-2.78 (m, 2H).

Example 250

2-Isopropyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (46 mg) was prepared according to Example 189 using208 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 187 mg of2-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₄H₁₉N₃S,261.13; found, m/z 262.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.70-7.69 (m,1H), 7.25-7.23 (m, 1H), 7.15-7.14 (m, 1H), 4.65 (br s, 2H), 4.55-4.49(m, 1H), 3.8-3.6 (m, 2H), 3.23-3.10 (m, 2H), 2.93-2.83 (m, 2H),1.44-1.36 (m, 6H).

Example 251

3-(2-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (90 mg) was prepared according to Example 189 using266 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 292 mg of2-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₂₀ClN₃, 289.13; found, m/z 290.4 [M+H]⁺, 292.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.65-7.63 (m, 1H), 7.58-7.49 (m, 2H), 7.41-7.39 (m, 1H),4.66 (br s, 2H), 4.16 (m, 1H), 4.00-3.44 (m, 2H), 3.0-2.6 (m, 2H),1.47-1.38 (m, 6H).

Example 252

1-[4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-ethanone

The title compound (168 mg) was prepared according to Example 189 using255 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 341 mg of4-acetylphenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₃N₃O, 297.18; found, m/z 298.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):8.17-8.15 (m, 1H), 7.69-7.67 (m, 1H), 7.51-7.49 (m, 1H), 7.37-7.35 (m,1H), 4.65 (br s, 1H), 4.46-4.38 (m, 1H), 4.00-3.50 (m, 2H), 3.48-3.42(m, 1H), 3.25-3.17 (m, 1H), 3.13-2.81 (m, 2H), 2.67 (s, 1.5H), 1.55 (s,1.5H), 1.44-1.40 (m, 6H).

Example 253

2-Isopropyl-3-(4-nitro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (34 mg) was prepared according to Example 189 using274 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 321 mg of4-nitrophenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₂₀N₄O₂, 300.16; found, m/z 301.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):8.42-8.40 (m, 2H), 7.62-7.60 (m, 2H), 4.37 (m, 1H), 3.43-3.41 (m, 2H),3.21-3.18 (m, 2H), 2.82-2.79 (m, 2H), 1.41 (d, J=8.2 Hz, 6H).

Example 254

3-(4-Chloro-phenyl)-1-cycloheptyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (22 mg) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.30 mmol) usingchloro-cycloheptane (1.0 mmol) in place of chloro-cyclobutane accordingto Example 238. The reaction sequence also yielded3-(4-chloro-phenyl)-2-cycloheptyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₂₆ClN₃, 343.18; found, m/z 344.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.40-7.34 (m, 4H), 4.31-4.27 (m, 1H), 3.39-3.37 (m, 2H),3.28-3.26 (m, 2H), 3.17-3.16 (m, 2H), 2.95-2.92 (m, 2H), 2.04-2.01 (m,2H), 1.92-1.90 (m, 2H), 1.77-1.75 (m, 2H), 1.63-1.53 (m, 6H).

Example 255

3-(4-Chloro-phenyl)-1-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (47 mg) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.30 mmol) usingchloro-cyclooctane (1.0 mmol) in place of chloro-cyclobutane accordingto Example 238. The reaction sequence also yielded3-(4-chloro-phenyl)-2-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₁ H₂₈ClN₃, 357.20; found, m/z 358.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.50-7.44 (m, 4H), 4.49-4.45 (m, 1H), 3.51-3.48 (m, 2H),3.38-3.36 (m, 2H), 3.33-3.32 (m, 2H), 3.05-3.04 (m, 2H), 2.21-2.18 (m,2H), 1.97-1.88 (m, 4H), 1.72-1.64 (m, 8H).

Example 256

2-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.023 g) was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g), as described inExample 60. MS (ESI): exact mass calculated for C₂₀H₂₀ClN₃, 337.13;found, m/z 338.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.47-7.44 (m, 2H),7.25-7.19 (m, 5H), 6.94-6.92 (m, 2H), 5.17 (s, 2H), 3.66 (s, 2H),3.21-3.19 (m, 2H), 2.93-2.90 (m, 2H), 1.93-1.84 (s, 2H).

Example 257

2-Ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (140 mg) was prepared according to Example 193 using213 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 232 mg of4-ethylphenylboronic acid. MS (ESI): exact mass calculated for C₁₇H₂₃N₃,269.19; found, m/z 270.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.40-7.39 (m,2H), 7.27-7.26 (m, 2H), 4.65 (br s, 2H), 4.05-4.00 (m, 2H), 3.8-3.6 (m,2H), 3.18-3.00 (m, 2H), 2.88-2.81 (m, 2H), 2.76-2.71 (m, 2H), 1.32-1.24(m, 6H).

Example 258

4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

The title compound (47 mg) was prepared according to Example 193 using205 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 218 mg of4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C₁₆H₁₈N₄,266.15; found, m/z 267.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.93-7.91 (m,2H), 7.58-7.56 (m, 2H), 4.03 (q, J=7.2 Hz, 2H), 3.43-3.40 (m, 2H),3.18-3.16 (m, 2H), 2.82-2.80 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).

Example 259

3-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (113 mg) was prepared from3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 190) and paraformaldehyde as in Example 35. MS (ESI): exactmass calculated for C₁₇H₂₂FN₃, 287.18; found, m/z 288.5 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.42-7.40 (m, 2H), 7.34-7.30 (m, 2H), 4.42 (m, 1H),3.77-3.74 (m, 1H), 3.67-3.62 (m, 2H), 3.36-3.34 (m, 1H), 3.27-3.21 (m,3H), 3.03 (s, 3H), 2.92-2.89 (m, 1H), 2.80-2.76 (m, 1H), 1.49-1.29 (m,6H).

Example 260

3-(4-Fluoro-phenyl)-2,6-diisopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (92 mg) was prepared from3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 190) and acetone as in Example 35. MS (ESI): exact masscalculated for C₁₉H₂₆FN₃, 315.21; found, m/z 316.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.42-7.39 (m, 2H), 7.33-7.30 (m, 2H), 4.40 (m, 1H),3.78-3.74 (m, 2H), 3.68-3.63 (m, 1H), 3.36-3.21 (m, 4H), 2.99-2.94 (m,1H), 2.80-2.76 (m, 1H), 1.54-1.37 (m, 12H).

Example 261

2-Ethyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (131 mg) was prepared according to Example 193 using205 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 245 mg of4-isopropylphenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₅N₃, 283.20; found, m/z 284.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.48-7.46 (m, 2H), 7.34-7.33 (m, 2H), 4.12 (q, J=7.3 Hz, 2H), 3.50-3.45(m, 2H), 3.36-3.33 (m, 2H), 3.27-3.25 (m, 2H), 3.01 (m, 1H), 2.87-2.85(m, 2H), 1.34 (t, J=7.3 Hz, 3H), 1.31 (d, J=6.9 Hz, 6H).

Example 262

2-Ethyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (134 mg) was prepared according to Example 193 using219 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 241 mg of4-methoxyphenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₂₁N₃O, 271.17; found, m/z 272.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.36-7.33 (m, 2H), 7.15-7.12 (m, 2H), 4.12 (q, J=7.3 Hz, 2H), 3.88 (s,3H), 3.49-3.47 (m, 2H), 3.36-3.34 (m, 2H), 3.28-3.25 (m, 2H), 2.88-2.85(m, 2H), 1.35 (t, J=7.3 Hz, 3H).

Example 263

2-Ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Ethyl-3-(4-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a 25 mL round bottom flask was added 216 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A), 139 mg of4-trifluoromethylphenylboronic acid, 17 mg of Bu₄N⁺Br⁻, 6 mg of dppf and17 mg of PdCl₂(dppf). Toluene (5 mL) was added, followed by 0.8 mL of 2M aq. Na₂CO₃, and the mixture was heated at 120° C. for 12 h under N₂.The mixture was filtered through diatomaceous earth and the filtrate wasconcentrated in vacuo to afford 294 mg of dark brown viscous oil.Chromatography on SiO₂ (0 to 25% EtOAc/hexanes) provided 177 mg of thedesired product. MS (ESI): exact mass calculated for C₂₁H₂₆F₃N₃O₂,409.20; found, m/z 410.5 [M+H]⁺.

Step B. The title compound (149 mg) was prepared according to Example43, Step E. MS (ESI): exact mass calculated for C₁₆H₁₈F₃N₃, 309.15;found, m/z 310.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.90-7.89 (m, 2H),7.65-7.63 (m, 2H), 4.67 (br s, 2H), 4.10 (q, J=7.2 Hz, 2H), 4.00-3.56(m, 2H), 3.36-3.24 (m, 2H), 2.95-2.85 (m, 2H), 1.33 (t, J=7.2 Hz, 3H).

Example 264

2-Ethyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (138 mg) was prepared according to Example 263 using206 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 95 mg of2-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₂₁N₃, 255.17; found, m/z 256.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.49-7.42 (m, 2H), 7.38-7.35 (m, 1H), 7.25-7.24 (m, 1H), 4.69 (br s,2H), 4.03-3.17 (m, 5H), 2.76-2.68 (m, 2H), 2.15 (s, 3H), 1.28 (t, J=7.2Hz, 3H).

Example 265

3-(2-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (73 mg) was prepared according to Example 263 using227 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 120 mg of2-chlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₅H₁₈ClN₃, 275.12; found, m/z 276.4 [M+H]⁺, 278.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.64-7.62 (m, 1H), 7.58-7.48 (m, 2H), 7.41-7.39 (m, 1H),3.97-3.86 (m, 2H), 3.44-3.42 (m, 2H), 3.20-3.17 (m, 2H), 2.70-2.63 (m,2H), 1.26 (t, J=7.2 Hz, 3H).

Example 266

2-Ethyl-3-(2-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (121 mg) was prepared according to Example 263 using205 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 97 mg of2-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₅H₁₈FN₃, 259.15; found, m/z 260.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.61-7.55 (m, 1H), 7.39-7.30 (m, 3H), 4.01-3.91 (m, 2H), 3.43-3.41 (m,2H), 3.18-3.16 (m, 2H), 2.79-2.73 (m, 2H), 1.28 (t, J=9.0 Hz, 3H).

Example 267

3-(2,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (37 mg) was prepared according to Example 189 using230 mg of2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 189, Step A) and 308 mg of2,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₁₉Cl₂N₃, 323.10; found, m/z 324.4 [M+H]⁺, 326.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.73-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.37-7.35 (m, 1H),4.65 (br s, 1H), 4.11-4.05 (m, 1H), 3.43-3.40 (m, 2H), 3.29-3.16 (m,3H), 2.70-263 (m, 2H), 1.39-1.32 (m, 6H).

Example 268

[4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-dimethyl-amine

The title compound (57 mg) was prepared according to Example 263 using205 mg of2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 193, Step A) and 115 mg of4-dimethylaminophenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₄N₄, 284.20; found, m/z 285.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.87-7.85 (m, 2H), 7.65-7.63 (m, 2H), 4.67 (br s, 2H), 4.06 (q, J=9.0Hz, 2H), 4.00-3.62 (m, 2H), 3.36 (s, 6H), 3.32-3.29 (m, 2H), 3.18-2.81(m, 2H), 1.31 (t, J=9.0 Hz, 3H).

Example 269

6-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (115 mg) was prepared from3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 190) and benzaldehyde as in Example 35. MS (ESI): exact masscalculated for C₂₃H₂₆FN₃, 363.21; found, m/z 364.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.58-7.55 (m, 2H), 7.53-7.51 (m, 3H), 7.37-7.33 (m, 2H),7.31-7.27 (m, 2H), 4.52 (s, 2H), 4.34 (m, 1H), 3.80-3.75 (m, 1H),3.68-3.64 (m, 1H), 3.35-3.16 (m, 4H), 2.83-2.80 (m, 2H), 1.38 (t, J=6.7Hz, 6H).

Example 270

3-(4-Fluoro-phenyl)-2-isopropyl-6-(3-phenyl-propyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (142 mg) was prepared from3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 190) and 3-phenyl-propionaldehyde as in Example 35. MS (ESI):exact mass calculated for C₂₅H₃₀FN₃, 391.24; found, m/z 392.5 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD): 7.45-7.41 (m, 2H), 7.35-7.26 (m, 6H), 7.22-7.19(m, 1H), 4.46 (m, 1H), 3.79-3.76 (m, 1H), 3.67-3.63 (m, 1H), 3.46-3.43(m, 1H), 3.35-3.29 (m, 5H), 2.90-2.87 (m, 1H), 2.83-2.73 (m, 3H),2.19-2.12 (m, 2H), 1.44 (t, J=6.7 Hz, 6H).

Example 271

3-(4-Fluoro-phenyl)-2-isopropyl-6-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (104 mg) was prepared from3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 190) and phenylacetaldehyde as in Example 35. MS (ESI): exactmass calculated for C₂₄H₂₈FN₃, 377.23; found, m/z 378.5 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.41-7.27 (m, 9H), 4.39 (m, 1H), 3.88-3.84 (m, 1H),3.73-3.71 (m, 1H), 3.56-3.52 (m, 3H), 3.45-3.20 (m, 3H), 3.17-3.14 (m,2H), 2.89-2.84 (m, 2H), 1.41 (t, J=6.6 Hz, 6H).

Example 272

3-(4-Fluoro-phenyl)-2-isopropyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester

This compound was obtained as an intermediate in the sequence describedfor Example 190. MS (ESI): exact mass calculated for C₂₁H₂₈F N₃O₂,373.46; found, m/z 374.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.24-7.13 (m,4H), 4.24 (m, 1H), 3.62-3.55 (m, 2H), 3.49-3.42 (m, 2H), 3.01-2.93 (m,2H), 2.52-2.44 (m, 2H),1.50-1.45 (m, 9H), 1.39 (d. J=6.9 Hz, 6H).

Example 273

1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulenecitrate salt

Step A. 5-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethylester. A dried, N₂-flushed, 500-mL, three-necked, round-bottomed flaskequipped with a magnetic stir bar, was charged with4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g, 0.10 mol) andBF₃.Et₂O (14 mL, 0.11 mol) in Et₂O (200 mL) and the mixture was chilledto −5° C. Slowly, ethyl diazoacetate (13.7 mL, 0.13 mol) was added overa period of 1 h causing vigorous gas evolution. The internal temperaturewas maintained between 0° C. and −5° C. during the addition. Thereaction was stirred for 1 h at 0° C., then slowly quenched with 30% aq.Na₂CO₃ at 0° C. The pH was adjusted to between 7 and 8 and then H₂O (30mL) was added to the mixture. The organic layer was extracted with EtOAc(2×75 mL), dried with Na₂SO₄, filtered, and concentrated to an orangeoil. The crude oil was purified by filtration chromatography (SiO₂: 14cm OD, 8 cm in height; 10 to 30% EtOAc/hexanes) to recover the titlecompound as light yellow oil (85%). MS (ESI): exact mass calculated forC₁₄H₂₃NO₅; found, m/z none, unstable. HPLC (Method B): R_(t)=8.53 min.¹H NMR (400 MHz, CDCl₃): 4.25-2.03 (m, 11H), 1.47-1.45 (d, J=7.8 Hz,9H), 1.31-1.24 (m, 3H).

Step B. 3-Oxo-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. In a 1-L, one-necked, round-bottomed flaskequipped with a magnetic stir bar was combined5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester(24.42 g, 85.0 mmol) and hydrazine (3.0 mL, 0.095 mol) in EtOH (250 mL).The resulting reaction mixture was heated at reflux for 4 h, then wasconcentrated to provide the desired pyrazole as a white solid in 95%crude yield. The crude pyrazole was used in the next step withoutfurther purification. MS (ESI): exact mass calculated for C₁₂H₁₉N₃O₃,253.14; found, m/z 254.1 [M+H]⁺. HPLC (Method B): R_(t)=6.48 min. ¹H NMR(400 MHz, CDCl₃): 3.64-3.54 (m, 4H), 2.91-2.86 (m, 2H), 2.70-2.65 (m,2H), 1.49 (s, 9H).

Step C.3-Trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. In a 250-mL, one-necked, round-bottomed flaskequipped with a magnetic stirring bar,N-phenyltrifluoromethanesulfonimide (50 g, 0.14 mol) was suspended in100 mL pyridine and then3-oxo-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylic acidtert-butyl ester (35.4 g, 0.14 mol) was added as a solid at rt. Thereaction mixture formed a homogeneous solution after 1 h and stirringwas continued at rt overnight (15 h). The solvent was evaporated undervacuum and then the residue was partitioned between Et₂O (500 mL) and 1M aq. K₂CO₃ (300 mL). The organic layer was separated and washed withaq. K₂CO₃ (1 mol/L, 300 mL) three times and then with brine (200 mL)once, dried over MgSO₄, and evaporated to afford the product as a whitesolid (50.2 g, 0.13 mol, 93%), which was used on next reaction withoutfurther purification. MS (ESI): exact mass calculated for C₁₃H₁₈F₃N₃O₅S,385.09; m/z found, 384.0 [M−H]⁻. HPLC (Method B): R_(t)=9.55 min. ¹H NMR(500 MHz, CDCl₃): 9.52 (s, 1H), 3.70-3.50 (m, 4H), 3.00-2.85 (m, 2H),2.70-2.60 (m, 2H), 1.49 (s, 9H).

Step D.1-Benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. In a 1-L, three-necked, round-bottomed flaskcontaining a magnetic stirring bar,3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (48 g, 0.125 mol) was dissolved in 500 mL of dryTHF under N₂. The solution was cooled to 0° C. and potassium t-butoxide(15.4 g, 0.137 mol) was added portion-wise as solid. The reactionmixture was stirred for 10 min to form a clear, homogeneous solution.Benzyl bromide (23.4 g, 0.137 mol) was added through an addition funnelover 10 min. The resulting mixture was stirred at rt overnight (15 h).The solvent was evaporated and the residue was re-dissolved in EtOAc(300 mL). The organic layer was washed with H₂O (2×200 mL) and then withbrine (200 mL), dried over MgSO₄, filtered, and concentrated. The crudeproduct was purified by pad-filtration through a plug of SiO₂ to affordthe pure product as a white solid (44.5 g, 94 mmol, 75%). MS (ESI):exact mass calculated for C₂₀H₂₄F₃N₃O₅S, 475.14; found, m/z 476.2[M+H]⁺. HPLC (Method B): R_(t)=10.90 min. ¹H NMR (500 MHz, CDCl₃):7.40-7.25 (m, 5H), 7.10-7.05 (m, 2H), 5.22-5.15 (m, 2H), 3.60-3.50 (m,4H), 2.80-2.60 (m, 4H), 1.47-1.42 (m, 9H).

Step E. 2-(4-Chloro-phenyl)-benzo[1,3,21dioxaborole. In a 250-mL,one-necked, round-bottomed flask equipped with a Dean-Stark trap and acondenser, the reaction solution of 4-chlorophenylboronic acid (17.5 g,0.112 mol) and catechol (12.3 g, 0.112 mol) in toluene (150 mL) washeated at reflux for 4 h. The solution was cooled to rt and a whitesolid precipitated. The solvent was evaporated and the crude product(25.8 g, 0.112 mol, 100%) was used as such in the next reaction withoutfurther purification. HPLC (Method B): R_(t)=6.00 and 7.50 min. ¹H NMR(500 MHz, CDCl₃): 8.01 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H),7.34-7.29 (m, 2H), 7.15-7.11 (m, 2H).

Step F.1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a 1-L, three-necked, round-bottomed flask wasadded Pd(dppf)Cl₂ (2.8 g, 3.4 mmol),1,1′-bis(diphenylphosphino)ferrocene (0.96 g, 1.73 mmol), Bu₄N⁺Br⁻ (2.78g, 8.6 mmol), Na₂CO₃ (36.5 g, 344 mmol) and2-(4-chloro-phenyl)-benzo[1,3,2]dioxaborole (23.8 g, 103 mmol), underN₂. A solution of1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (41 g, 86 mmol) in toluene (250 mL) was added,followed by the addition of H₂O (250 mL) via syringe. The reactionmixture was stirred at reflux for 3 h and then was cooled to rt. Theorganic layer was diluted with EtOAc (200 mL) and then was washed with 1M aq. K₂CO₃ until the color of the aqueous layer stabilized. The organiclayer was washed with brine (200 mL), dried over MgSO₄, filtered, andconcentrated. The crude product thus obtained was pad-filtered through ashort plug of SiO₂ to afford the title compound (34.5, 79 mmol, 92%) asa white solid. MS (ESI): exact mass calculated for C₂₅H₂₈ClN₃O₂, 437.19;found, m/z 438.1, [M+H]⁺. HPLC (Method B): R_(t)=10.89 min. ¹H NMR (400MHz, CDCl₃): 7.50-7.45 (m, 2H), 7.40-7.36 (m, 2H), 7.36-7.25 (m, 3H),7.13-7.10 (m, 2H), 5.35-5.33 (m, 2H), 3.56-3.50 (m, 4H), 2.83-2.75 (m,4H), 1.28-1.25 (m, 9H).

Step G.1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.In a 500-mL, one-necked, round-bottomed flask,1-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (34 g, 77 mmol) was dissolved in CH₂Cl₂ (100 mL).Trifluoroacetic acid (70 mL) was added carefully. The reaction mixturewas stirred at rt for 2 h. The solvent was evaporated and the residuewas re-dissolved in CH₂Cl₂ (200 mL). Sat. aq. NaHCO₃ solution was addedslowly until CO₂ evolution ceased. The aqueous layer was extracted withCH₂Cl₂ (2×200 mL). The organic layers were combined, dried over MgSO₄,filtered, and concentrated. The crude product was recrystallized fromhot EtOAc to afford the pure product as a white solid (24 g, 71 mmol,91%). MS (ESI): exact mass calculated for C₂₀H₂₀ClN₃, 337.13; found, m/z338.3 [M+H]⁺. HPLC (Method B): R_(t)=7.53 min. ¹H NMR (400 MHz, CDCl₃):7.48-7.44 (m, 2H), 7.44-7.38 (m, 3H), 7.38-7.27 (m, 3H), 7.14-7.06 (m,2H), 5.36 (s, 2H), 3.30-3.16 (m, 4H), 3.10-2.98 (m, 4H).

Step H.1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulenecitrate salt. In a 500-mL, one-necked, round-bottomed flask,1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene7 (10 g, 30 mmol) was suspended in MeOH (70 mL), and the mixture washeated until a homogeneous solution formed. A solution of citric acidmonohydrate (7.5 g, 36 mmol) in MeOH (10 mL) was added dropwise. Theresulting homogeneous solution was heated at reflux for 20 min and thenwas cooled to rt. The solvent was evaporated to form an oil. The oil wasdiluted with EtOAc (200 mL) and the mixture was heated to reflux. Tothis hot solution MeOH was slowly added to form a slurry. The slurry wascooled to rt and the precipitated solids were collected by filtration,washed with EtOAc, and dried under vacuum to afford the citrate salt(1:1 ratio based on ¹HNMR analysis, 9.1 g). The filtrate wasconcentrated and the above procedure to form the citrate salt wasrepeated by adding another 0.5 equivalents of citric acid to affordanother 2 g of product. The combined yield was 71%. ¹H NMR (500 MHz,D₂O): 7.35-7.22 (m, 4H), 7.22-7.15 (m, 3H), 7.0-6.92 (m, 2H), 5.22 (s,2H), 3.22-3.14 (m, 4H), 3.0-2.92 (m, 2H), 2.88-2.80 (m, 2H), 2.69 (d,J=15 Hz, 2H), 2.57 (d, J=15 Hz, 2H).

Example 274

3-(4′-Chloro-biphenyl-4-yl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (18 mg) was also obtained from Example 187, Step B.MS (ESI): exact mass calculated for C₂₁H₁₉ClF₃N₃, 405.12; found, m/z406.1 [M+H]⁺, 408.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.74-7.72 (m, 2H),7.61-7.59 (m, 2H), 7.41-7.35 (m, 4H), 4.70-4.55 (m, 3H), 3.85-3.30 (m,3H), 3.25-3.05 (m, 2H), 2.82-2.74 (m, 2H).

Example 275

3-(4′-Chloro-biphenyl-4-yl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (33 mg) was also obtained from Example 181. MS (ESI):exact mass calculated for C₂₄H₂₆ClN₃, 391.18; found, m/z 392.1 [M+H]⁺,394.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.81-7.80 (m, 2H), 7.70-7.68 (m,2H), 7.50-7.41 (m, 4H), 4.65-4.53 (m, 3H), 3.85-3.67 (m, 2H), 3.30-3.10(m, 2H), 2.88 (br s, 2H), 2.01-1.91 (m, 6H), 1.63-1.60 (m, 2H).

Example 276

2-Cyclobutyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using cyclobutylhydrazine hydrochloride (made fromcyclobutanone as shown in Example 177, Step A) in place ofphenylhydrazine and t-butanol in place of EtOH, with the addition of 3equiv of triethylamine.

Step B. The title compound (118 mg) was prepared according to Example263 using 189 mg of the product from Step A and 73 mg of phenylboronicacid. MS (ESI): exact mass calculated for C₁₇H₂₁N₃, 267.17; found, m/z268.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.60-7.50 (m, 3H), 7.34-7.30 (m,2H), 4.71-4.63 (m, 2H), 4.00-3.40 (m, 2H), 3.24-3.22 (m, 3H), 3.00-2.80(m, 2H), 2.68-2.59 (m, 2H), 2.30-2.24 (m, 2H), 2.30-2.24 (m, 2H),1.84-1.71 (m, 2H).

Example 277

2-Cyclobutyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (122 mg) was prepared according to Example 263 using198 mg of2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 276, Step A) and 88 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₀FN₃, 285.16; found, m/z 286.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.35-7.27 (m, 4H), 4.65-4.59 (m, 2H), 3.95-3.3.40 (m, 2H), 3.32-3.05 (m,3H), 3.00-2.75 (m, 2H), 2.67-2.59 (m, 2H), 2.29-2.23 (m, 2H), 1.84-1.73(m, 2H).

Example 278

2-Cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (117 mg) was prepared according to Example 263 using192 mg of2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 276, Step A) and 83 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₃N₃, 281.19; found, m/z 282.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.41-7.32 (m, 2H), 7.23-7.13 (m, 2H), 4.71-4.65 (m, 2H), 4.00-3.41 (m,2H), 3.32-3.05 (m, 3H), 2.95-2.79 (m, 2H), 2.67-2.58 (m, 2H), 2.43 (s,3H), 2.28-2.23 (m, 2H), 1.84-1.71 (m, 2H).

Example 279

2-Cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (73 mg) was prepared according to Example 263 using201 mg of2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 276, Step A) and 122 mg of4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₀F₃N₃, 335.16; found, m/z 336.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.86-7.85 (m, 2H), 7.52-7.50 (m, 2H), 4.65-4.58 (m, 1H), 3.45-3.41 (m,2H), 3.22-3.20 (m, 2H), 2.81-2.79 (m, 2H), 2.67-2.62 (m, 2H), 2.30-2.24(m, 2H), 1.84-1.74 (m, 2H).

Example 280

4-(2-Cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

The title compound (28 mg) was prepared according to Example 263 using172 mg of2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 276, Step A) and 172 mg of4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C₁₈H₂₀H₄,292.17; found, m/z 293.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.92-7.90 (m,2H), 7.50-7.48 (m, 2H), 4.65-4.58 (m, 1H), 3.42-3.40 (m, 2H), 3.21-3.19(m, 2H), 2.81-2.78 (m, 2H), 2.66-2.62 (m, 2H), 2.30-2.25 (m, 2H),1.85-1.74 (m, 2H).

Example 281

2-Cyclopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. N′-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester. To asolution of 1.37 g of 3-(4-cyano-phenyl)-oxaziridine-2-carboxylic acidtert-butyl ester in Et₂O (8 mL) was added 1.2 mL of cyclopropylamine.The mixture was aged for 2 h and then concentrated in vacuo.Chromatography on SiO₂ (0 to 25% EtOAc/hexanes) provided an impure paleyellow solid that was sublimed under high vacuum in a 50° C. oil bath toafford 641 mg of the desired compound. ¹H NMR (500 MHz, CDCl₃): 6.31 (brs, 1H), 3.49 (br s, 1H), 2.74 (br s, 1H), 1.48 (s, 9H), 0.52-0.48 (m,4H).

Step B. Cyclopropyl-hydrazine hydrochloride. To a solution of theproduct from Step A (636 mg) in CH₂Cl₂ (10 mL) was added 9 mL of 4.0 MHCl in 1,4-dioxane. The mixture was aged for 12 h and then concentratedin vacuo to provide 507 mg of the title compound. ¹H NMR (500 MHz,CD₃OD): 2.61-2.57 (m, 1H), 0.71-0.59 (m, 4H).

Step C.2-Cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared as in Steps Aand B of Example 176, using cyclopropyl-hydrazine hydrochloride in placeof phenylhydrazine and t-butanol in place of EtOH, with the addition of3 equiv. of triethylamine.

Step D. The title compound (128 mg) was prepared according to Example263 using 208 mg of2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester and 84 mg of phenylboronic acid. MS (ESI): exactmass calculated for C₁₆H₁₉N₃, 253.16; found, m/z 254.4 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.57-7.44 (m, 5H), 3.57-3.54 (m, 1H), 3.42-3.40 (m,2H), 3.17-3.14 (m, 2H), 2.93-2.84 (m, 2H), 0.91-0.85 (m, 4H).

Example 282

2-Cyclopropyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (134 mg) was prepared according to Example 281 using200 mg of2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 281, Step C) and 92 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₆H₁₈FN₃, 271.15; found, m/z 272.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.51-7.47 (m, 2H), 7.31-7.27 (m, 2H), 3.55-3.51 (m, 1H), 3.41-3.39 (m,2H), 3.23-3.14 (m, 2H), 3.00-2.83 (m, 2H), 0.93-.084 (m, 4H).

Example 283

2-(1-Ethyl-propyl)-3-(4-fluoro-3-methyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (34 mg) was prepared according to Example 183 using59 mg of2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 183, Step A) and 19 mg of4-fluoro-3-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₉H₂₆FN₃, 315.21; found, m/z 316.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.27-7.18 (m, 3H), 4.69-4.65 (m, 1H), 3.93-3.89 (m, 1H), 3.50-3.27 (m,5H), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.87 (m, 2H), 1.83-1.76 (m,2H), 0.81-0.68 (m, 6H).

Example 284

2-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (133 mg) was prepared according to Example 281 using200 mg of2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 281, Step C) and 90 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₁N₃, 267.17; found, m/z 268.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.42-7.34 (m, 4H), 4.68-4.65 (m, 2H), 3.80-3.30 (m, 6H), 2.97 (br s,2H), 2.44 (s, 3H), 0.94-0.91 (m, 4H).

Example 285

2-Cyclopropyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (134 mg) was prepared according to Example 281 using200 mg of2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 281, Step C) and 84 mg of3-thiopheneboronic acid. MS (ESI): exact mass calculated for C₁₄H₁₇N₃S,259.11; found, m/z 260.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.64-7.63 (m,2H), 7.31-7.29 (m, 1H), 4.65 (br s, 1H), 3.70-3.60 (br s, 1H), 3.57-3.52(m, 1H), 3.40-3.38 (m, 1H), 3.19 (br s, 1H), 3.13-3.11 (m, 1H),2.99-2.96 (m, 1H), 2.91-2.89 (m, 1H), 0.93-0.88 (m, 4H).

Example 286

4-(2-Cyclopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile

The title compound (91 mg) was prepared according to Example 281 using200 mg of2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 281, Step C) and 97 mg of4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C₁₇H₁₈N₄,278.15; found, m/z 279.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.94-7.92 (m,2H), 7.71-7.70 (m, 2H), 4.66 (br s, 1H), 3.71-3.68 (m, 1H), 3.47 (br s,1H), 3.39-3.19 (m, 4H), 3.01-2.88 (m, 2H), 0.96-0.90 (m, 4H).

Example 287

6-Benzyl-2-isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

Step A. Trifluoro-methanesulfonic acid6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-ylester. The desired triflate was prepared as in Step A of Example 189,using 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester in placeof the product from Example 59, Step A.

Step B. The title compound (54 mg) was prepared as in Example 263 using200 mg of trifluoro-methanesulfonic acid6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-ylester and 85 mg of phenylboronic acid. MS (ESI): exact mass calculatedfor C₂₂H₂₅N₃, 331.20; found, m/z 332.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.60-7.48 (m, 7H), 7.39-7.37 (m, 2H), 4.59-4.48 (m, 3H), 4.44-4.34 (m,2H), 3.81-3.79 (m, 1H), 3.46-3.40 (m, 1H), 2.94-2.84 (m, 2H), 1.46-1.29(m, 6H).

Example 288

2-Isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

To a solution of the compound (98 mg) from Example 287, Step B in 5 mLof EtOH was added 98 mg of 10% Pd/C followed by 0.14 mL of1,4-cyclohexadiene. The mixture was placed under N₂ and heated in an 80°C. oil bath for 5 h. The mixture was filtered and the filtrate wasconcentrated in vacuo to provide 67 mg of viscous colorless oil.Chromatography on SiO₂ (0 to 8% 2 M NH₃ in MeOH/EtOAc) afforded 59 mg ofthe title compound. The product (59 mg) was dissolved in Et₂O andtreated with excess 1.0 M HCl in Et₂O for 30 min. The solvent wasremoved in vacuo to afford 68 mg of the corresponding HCl salt. MS(ESI): exact mass calculated for C₁₅H₁₉N₃, 241.16; found, m/z 242.4[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.57-7.48 (m, 3H), 7.38-7.36 (m, 2H),4.53 (m, 1H), 4.40-4.32 (m, 2H), 3.47 (t, J=6.2 Hz, 2H), 2.82 (t, J=6.2Hz, 2H), 1.41 (d, J=6.7 Hz, 6H).

Example 289

6-Benzyl-2-isopropyl-3-thiophen-3-yl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

The title compound (69 mg) was prepared according to Example 287 using300 mg of trifluoro-methanesulfonic acid6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-ylester and 133 mg of 3-thiopheneboronic acid. MS (ESI): exact masscalculated for C₂₀H₂₃N₃S, 337.16; found, m/z 338.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.66-7.65 (m, 1H), 7.60-7.57 (m, 3H), 7.55-7.53 (m, 3H),7.21-7.20 (m, 1H), 4.65-4.52 (m, 3H), 4.42-4.33 (m, 2H), 3.82-3.79 (m,1H), 3.44-3.40 (m, 1H), 2.94-2.91 (m, 2H), 1.46-1.35 (m, 6H).

Example 290

6-Benzyl-2-isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

The title compound (67 mg) was prepared according to Example 287 using300 mg of trifluoro-methanesulfonic acid6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-ylester and 141 mg of 4-methylphenylboronic acid. MS (ESI): exact masscalculated for C₂₃H₂₇N₃, 345.22; found, m/z 346.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.60-7.58 (m, 2H), 7.54-7.53 (m, 3H), 7.37-7.35 (m, 2H),7.28-7.24 (m, 2H), 4.58-4.49 (m, 3H), 4.42-4.33 (m, 2H), 3.81-3.78 (m,1H), 3.45-3.41 (m, 1H), 2.90-2.82 (m, 2H), 2.41 (s, 3H), 1.42-1.29 (m,6H).

Example 291

6-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

The title compound (72 mg) was prepared according to Example 287 using300 mg of trifluoro-methanesulfonic acid6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-ylester and 146 mg of 4-fluorophenylboronic acid. MS (ESI): exact masscalculated for C₂₂H₂₄FN₃, 349.20; found, m/z 350.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.60-7.57 (m, 2H), 7.55-7.53 (m, 3H), 7.43-7.40 (m, 2H),7.32-7.27 (m, 2H), 4.59-4.34 (m, 5H), 3.81-3.79 (m, 1H), 3.46-3.40 (m,1H), 2.90-2.85 (m, 2H), 1.43-1.36 (m, 6H).

Example 292

3-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

The title compound (101 mg) was prepared according to Example 288 using153 mg of6-benzyl-3-(4-fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridinein place of the product of Example 287, Step B. MS (ESI): exact masscalculated for C₁₅H₁₈FN₃, 259.15; found, m/z 260.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.42-7.28 (m, 4H), 4.50-4.47 (m, 1H), 4.35 (br s, 2H),3.49-3.46 (m, 2H), 2.81-2.79 (m, 2H), 1.42-1.36 (m, 6H).

Example 293

2-Isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

The title compound (114 mg) was prepared according to Example 288 using163 mg of6-benzyl-2-isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridinein place of the product of Example 287, Step B. MS (ESI): exact masscalculated for C₁₆H₂₁ N₃, 255.17; found, m/z 256.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.43-7.32 (m, 2H), 7.30-7.20 (m, 2H), 4.52 (m, 1H),4.39-4.31 (m, 2H), 3.47 (t, J=6.2 Hz, 2H), 2.80 (t, J=6.2 Hz, 2H), 1.42(d, J=6.6 Hz, 6H.

Example 294

2-Cyclopentyl-3-(4-fluoro-phenyl)-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. Trifluoro-methanesulfonic acid2-cyclopentyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester. The desired triflate was prepared as in Step A of Example 180using 2,2,7,7-tetramethyl-5-oxo-azepane-4-carboxylic acid ethyl ester(made from 2,2,6,6-tetramethyl-piperidin-4-one as shown in Step A ofExample 59) in place of 5-oxo-azepane-1,4-dicarboxylic acid tert-butylester 4-ethyl ester.

Step B. The title compound was prepared as in Step A of Example 263,using 216 mg of trifluoro-methanesulfonic acid2-cyclopentyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester and 103 mg of 4-fluorophenylboronic acid. The product (134 mg) wasdissolved in Et₂O and treated with excess 1.0 M HCl in Et₂O for 30 min.The solvent was removed in vacuo to afford 146 mg of the correspondingHCl salt. MS (ESI): exact mass calculated for C₂₂H₃₀FN₃, 355.24; found,m/z 356.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.36-7.26 (m, 4H), 4.47-4.41(m, 1H), 3.15 (s, 2H), 2.71 (s, 2H), 2.03-1.88 (m, 6H), 1.61-1.57 (m,2H), 1.44 (s, 6H), 1.35 (s, 6H).

Example 295

2-Cyclopentyl-5,5,7,7-tetramethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (129 mg) was prepared as in Example 294, using 263 mgof trifluoro-methanesulfonic acid2-cyclopentyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester and 110 mg of phenylboronic acid. MS (ESI): exact mass calculatedfor C₂₂H₃₁N₃, 337.25; found, m/z 338.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.56-7.49 (m, 3H), 7.32-7.30 (m, 2H), 4.51-4.44 (m, 1H), 3.12 (s, 2H),2.72 (s, 2H), 2.03-1.88 (m, 6H), 1.61-1.57 (m, 2H), 1.45 (s, 6H), 1.35(s, 6H).

Example 296

2-Isopropyl-5,5,7,7-tetramethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. Trifluoro-methanesulfonic acid2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester. The desired triflate was prepared as in Step A of Example 294using isopropylhydrazine in place of cyclopentylhydrazine.

Step B. The title compound (98 mg) was prepared as in Step B of Example294 using 196 mg trifluoro-methanesulfonic acid2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester and 87 mg of phenylboronic acid. MS (ESI): exact mass calculatedfor C₂₀H₂₉N₃, 311.24; found, m/z 312.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.57-7.52 (m, 3H), 7.32-7.31 (m, 2H), 4.34 (m, 1H), 3.11 (s, 2H), 2.71(s, 2H), 1.49-1.34 (m, 18H).

Example 297

3-(4-Fluoro-phenyl)-2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (100 mg) was prepared as in Example 296 using 196 mgof trifluoro-methanesulfonic acid2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester and 100 mg of 4-fluorophenylboronic acid. MS (ESI): exact masscalculated for C₂₀H₂₈FN₃, 329.23; found, m/z 330.5 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.36-7.27 (m, 4H), 4.31 (m, 1H), 3.10 (s, 2H), 2.70 (s,2H), 1.47-1.34 (m, 18H).

Example 298

2-sec-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-sec-Butyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The desired triflate was prepared according toExample 189, Step A, using sec-butylhydrazine hydrochloride (made from2-butanone as shown in Example 177, Step A) in place ofisopropylhydrazine hydrochloride.

Step B. The title compound (97 mg) was prepared as in Example 263 using216 mg of the triflate from Step A and 106 mg of phenylboronic acid. MS(ESI): exact mass calculated for C₁₇H₂₃N₃, 269.38; found, m/z 270.5[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.58-7.50 (m, 3H), 7.35-7.31 (m, 2H),4.15-4.07 (m, 1H), 3.50-3.18 (m, 6H), 2.88-2.73 (m, 2H), 1.97-1.86 (m,1H), 1.74-1.65 (m, 1H), 1.43 (d, J=6.8 Hz, 3H), 0.64 (t, J=7.4 Hz, 3H).

Example 299

2-sec-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (71 mg) was prepared as in Example 263 using 245 mgof the triflate from Example 298, Step A, and 153 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₂FN₃, 287.38; found, m/z 288.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.41-7.35 (m, 2H), 7.34-7.28 (m, 2H), 4.12-4.03 (m, 1H), 3.51-3.20 (m,6H), 2.90-2.73 (m, 2H), 1.97-1.87 (m, 1H), 1.75-1.65 (m, 1H), 1.44 (d,J=6.6 Hz, 3H), 0.66 (t, J=7.4 Hz, 3H).

Example 300

2-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (116 mg) was prepared as in Example 263 using 249 mgof the triflate from Example 298, Step A, and 129 mg of4-methylphenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₅N₃, 283.41; found, m/z 284.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.42-7.37 (m, 2H), 7.27-7.21 (m, 2H), 4.23-4.12 (m, 1H), 3.55-3.23 (m,6H), 2.92-2.75 (m, 2H), 2.43 (s, 3H), 1.98-1.88 (m, 1H), 1.77-1.68 (m,1H), 1.46 (d, J=6.6 Hz, 3H), 0.67 (t, J=7.4 Hz, 3H).

Example 301

2-sec-Butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (71 mg) was prepared as in Example 263 using 257 mgof the triflate from Example 298, Step A, and 175 mg of4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated forC₁₈H₂₂F₃N₃, 337.38; found, m/z 338.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.91-7.85 (m, 2H), 7.61-7.54 (m, 2H), 4.11-4.03 (m, 1H), 3.52-3.20 (m,6H), 2.93-2.75 (m, 2H), 1.99-1.88 (m, 1H), 1.75-1.65 (m, 1H), 1.45 (d,J=6.6 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H).

Example 302

2-Cyclopentyl-3-(4-fluoro-phenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (186 mg) was prepared from 216 mg of the product ofExample 182 according to Example 208. The product was dissolved in Et₂Oand treated with excess 1.0 M HCl in Et₂O to afford the correspondingHCl salt. MS (ESI): exact mass calculated for C₁₉H₂₄FN₃, 313.41; found,m/z 314.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.38-7.34 (m, 2H), 7.31-7.26(m, 2H), 4.47 (m, 1H), 3.75-3.69 (m, 1H), 3.64-3.57 (m, 1H), 3.33-3.15(m, 4H), 3.02 (s, 3H), 2.91-2.83 (m, 1H), 2.78-2.71 (m, 1H), 2.04-1.84(m, 6H), 1.65-1.54 (m, 2H).

Example 303

4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzamide

The title compound (26 mg) was prepared as in Example 263 using 206 mgof the triflate from Example 189, Step A, and 135 mg of 4-benzamideboronic acid. MS (ESI): exact mass calculated for C₁₇H₂₂N₄O, 298.38;found, m/z 299.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.93-7.89 (m, 2H),7.37-7.34 (m, 2H), 6.16 (br s, 1H), 5.81 (br s, 1H), 4.27 (m, 1H),3.05-3.00 (m, 2H), 2.97-2.88 (m, 4H), 2.51-2.46 (m, 2H), 1.41 (d, J=6.6Hz, 6H).

Example 304

2-Isopropyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A.2-Isopropyl-3-[4-(1H-tetrazol-5-)-phenyl]-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. A toluene solution of3-(4-cyano-phenyl)-2-isopropyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (intermediate in Example 212) and tributyltinazide was heated at reflux for 48 h. The mixture was concentrated andthe residue was purified on SiO₂ (0 to 75% EtOAc/hexanes) to afford 89mg of desired tetrazole as a glass.

Step B. The product from Step A was dissolved in dioxane and treatedwith HCl (4 M in dioxane, 1 mL) and mixture was stirred at RT. After 48h, the liquid was decanted and the solids washed with dioxane and driedunder vacuum to afford 60 mg of the title compound. MS (ESI): exact masscalculated for C₁₇H₂₁N₇, 323.40; found, m/z 324.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 8.24-8.20 (m, 2H), 7.58-7.55 (m, 2H), 4.42 (m, 1H),3.44-3.40 (m, 2H), 3.34-3.30 (m, 2H), 3.21-3.17 (m, 2H), 2.84-2.80 (m,2H), 1.42 (d, J=6.8, 6H).

Example 305

6-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. Trifluoro-methanesulfonic acid6-benzyl-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-ylester. The desired triflate was prepared as in Step A of Example 189using 1-benzyl-6-methyl-5-oxo-azepane-4-carboxylic acid ethyl ester(made from 1-benzyl-3-methyl-piperidin-4-one as shown in Step A ofExample 59) in place of 5-oxo-azepane-1,4-dicarboxylic acid tert-butylester 4-ethyl ester.

Step B. The title compound (29 mg) was prepared as in Example 287, StepB, from 151 mg of the triflate from Step A and 110 mg of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₂₄H₂₈FN₃, 377.50; found, m/z 378.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.41-7.37 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.18 (m, 3H), 7.16-7.10 (m,2H), 4.24 (m, 1H), 3.78 (d, J=13.4 Hz, 1H), 3.70 (d, J=13.4 Hz, 1H),3.19-3.12 (m, 1H), 2.78-2.68 (m, 3H), 2.55-2.43 (m, 3H), 1.40 (d, J=6.6,3H), 1.37 (d, J=6.6, 3H), 1.33 (d, J=7.1, 3H).

Example 306

3-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. 3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. Toa −78° C. solution of of 4-oxo-piperidine-1-carboxylic acid tert-butylester in THF (100 mL) was added LDA (50 mL, 1.8 M in THF) with stirringover 1 h. Methyl iodide was then added (5 mL) and the mixture wasallowed to warm slowly to RT and was stirred for 24 h. The reaction wasquenched by the addition of satd. aq. NH₄Cl (20 mL). The mixture waspoured into H₂O (800 mL), extracted with EtOAc, and concentrated.Purification on SiO₂ (120 g, 0 to 10% EtOAc/hexanes) gave 3.83 g of thedesired product as an off-white solid. ¹H NMR (500 MHz, CDCl₃):4.23-4.14 (m, 2H), 3.31-3.21 (m, 1H), 2.61-2.37 (m, 4H), 1.50 (s, 9H),1.05 (d, J=6.6 Hz, 3H).

Step B.2-Isopropyl-8-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The product from Step A (2.01 g) was treated withethyl diazoacetate (1.5 mL) as in Step A of Example 59. The resultingmaterial (2.90 g) was then transformed to the desired triflate (2.68 g)as shown in Step A of Example 189. The reaction sequence also produced0.60 g of2-isopropyl-4-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester.

Step C. The title compound (1.62 g) was prepared as in Step A of Example263 from 2.68 g of the triflate of Step B and 1.36 g of4-fluorophenylboronic acid. The coupling product was treated with TFA(20 mL) in 50 mL of CH₂Cl₂ for 16 h. The mixture was concentrated andthe residue was diluted with 1 M NaOH (50 mL) and extracted with CH₂Cl₂(50 mL, 3×). The combined organic layers were dried over Na₂SO₄ andconcentrated to provide the desired material. MS (ESI): exact masscalculated for C₁₇H₂₂FN₃, 287.18; found, m/z 288.4 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.18-7.05 (m, 4H), 4.16 (m, 1H), 3.08-2.97 (m, 2H),2.96-2.83 (m, 2H), 2.78-2.71 (m, 1H), 2.49-2.31 (m, 2H), 1.34 (d, J=6.6Hz, 3H), 1.31 (d, J=6.6 Hz, 3H), 1.29 (d, J=7.3 Hz, 3H).

Example 307

3-(4-Fluoro-phenyl)-2-isopropyl-4-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (154 mg) was prepared as in Example 177, Steps C andD, from 0.60 g of the triflate of Example 306, Step B, and 0.57 g of4-fluorophenylboronic acid. MS (ESI): exact mass calculated forC₁₇H₂₂FN₃, 287.18; found, m/z 288.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.25-7.20 (m, 2H), 7.17-7.12 (m, 2H), 4.15 (m, 1H), 3.35-3.30 (m, 1H),3.08-3.03 (m, 1H), 3.00-2.85 (m, 3H), 2.77-2.71 (m, 1H), 2.57-2.51 (m,1H), 1.39 (d, J=6.6 Hz, 3H), 1.36 (d, J=6.6 Hz, 3H), 1.15 (d, J=7.3 Hz,3H).

Example 308

2-Cyclopentyl-3-(4-fluoro-phenyl)-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

Step A. 2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. Asolution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acidtert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. andsec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellowsolution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was addedand the mixture was warmed from −78° C. to RT over 16 h. The reactionmixture was poured into water (800 mL) and extracted with EtOAc. Thecombined organic extracts were washed with H₂O, brine, and dried overNa₂SO₄. Purification on SiO₂ (330 g, 5 to 20% EtOAc/hexanes) provided1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acidtert-butyl ester. Multiple aliquots of this ester were combined (2.29g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at65° C. for 6 h. The solvent was removed and the residue was dissolved inCH₂Cl₂ and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, themixture was diluted with satd. aq. NaHCO₃ and H₂O, and extracted withCH₂Cl₂. Purification on SiO₂ (120 g, 5 to 15% EtOAc/hexanes) provided1.40 g of the desired product as a white solid. ¹H NMR (500 MHz, CDCl₃):4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m,1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s,9H), 1.11 (d, J=7.1 Hz, 3H).

Step B.2-Cyclopentyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. The product from Step A (1.40 g) was treated withethyl diazoacetate as in Step A of Example 59. The resulting material(1.0 g) was transformed to the desired triflate (0.78 g) as outlined inStep A of Example 180. The reaction sequence also produced2-cyclopentyl-5-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester.

Step C. The title compound (160.4 mg) was prepared as in Example 263from 301 mg of the triflate from Step B and 185 mg of4-fluorophenylboronic acid. The sequence also produced2-cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.The isomers were separated by SFC chromotagraphy. MS (ESI): exact masscalculated for C₁₉H₂₄FN₃, 313.41; found, m/z 314.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.25-7.21 (m, 2H), 7.18-7.12 (m, 2H), 4.22 (m, 1H),3.24-3.18 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.67 (m, 2H), 2.60-2.52 (m,1H), 2.45-2.39 (m, 1H), 2.16-1.82 (m 6H), 1.59-1.47 (m, 2H), 1.25 (d,J=6.3 Hz, 3H).

Example 309

2-Cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (3.8 mg) was prepared as outlined in Example 308. MS(ESI): exact mass calculated for C₁₉H₂₄FN₃, 313.41; found, m/z 314.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.24-7.19 (m, 2H), 7.18-7.13 (m, 2H),4.31 (m, 1H), 3.42-3.35 (m, 1H), 3.09-2.90 (m, 4H), 2.57-2.45 (m, 2H),2.14-1.80 (m 6H), 1.58-1.48 (m, 2H), 1.22 (d, J=6.3 Hz, 3H).

Example 310

2-Cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (64 mg) was prepared from 193 mg of the triflate fromExample 308, Step B, and 117 mg of 4-methylphenylboronic acid. MS (ESI):exact mass calculated for C₂₀H₂₇N₃, 309.45; found, m/z 310.4 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.28-7.25 (m, 2H), 7.17-7.13 (m, 2H), 4.39 (m,1H), 3.21-3.16 (m, 1H), 3.03-2.92 (m, 2H), 2.74-2.67 (m, 2H), 2.59-2.52(m, 1H), 2.49-2.43 (m, 1H), 2.40 (s, 3H), 2.17-1.82 (m, 6H), 1.59-1.47(m, 2H), 1.24 (d, J=6.3 Hz, 3H).

Example 311

2-Isopropyl-7-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (102 mg) was prepared as in Example 263 using 260 mgof2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (as outlined in Example 308 replacing cyclopentylhydrazine with isopropyl hydrazine) and 101 mg of phenylboronic acid.The reaction sequence also yielded2-isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.MS (ESI): exact mass calculated for C₁₇H₂₃N₃, 269.19; found, m/z 270.5[M+H]⁺. ¹H NMR (600 MHz, CD₃OD): 7.58-7.52 (m, 3H), 7.36-7.35 (m, 2H),4.43 (m, 1H), 3.65-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.23-3.11 (m, 3H),2.87-2.82 (m, 2H), 2.76-2.73 (m, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.43-1.40(m, 6H).

Example 312

2-Isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (28 mg) was prepared as in Example 311 and purifiedby SFC chromatography. MS (ESI): exact mass calculated for C₁₇H₂₃N₃,269.19; found, m/z 270.4 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): 7.58-7.52 (m,3H), 7.35-7.33 (m, 2H), 4.40 (m, 1H), 3.63-3.59 (m, 1H), 3.5-3.47 (m,1H), 3.31-3.19 (m, 3H), 2.80-2.68 (m, 2H), 1.43-1.39 (m, 6H), 1.34 (d,J=6.6 Hz, 3H).

Example 313

3-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (127 mg) was prepared as in Example 311 using 260 mgof2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester and 115 of 4-fluorophenylboronic acid. Thereaction sequence also yielded3-(4-fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.MS (ESI): exact mass calculated for C₁₇H₂₂FN₃, 287.18; found, m/z 288.5[M+H]⁺. ¹H NMR (600 MHz, CD₃OD): 7.39-7.37 (m, 2H), 7.32-7.28 (m, 2H),4.36 (m, 1H), 3.61-3.56 (m, 1H), 3.50-3.47 (m, 1H), 3.20-3.08 (m, 3H),2.85-2.80 (m, 1H), 2.73-2.69 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.41-1.38(m, 6H).

Example 314

3-(4-Fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (36 mg) was prepared as in Example 311 and purifiedby chromatography on SFC. MS (ESI): exact mass calculated for C₁₇H₂₂FN₃,287.18; found, m/z 288.5 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): 7.37-7.35 (m,2H), 7.31-7.28 (m, 2H), 4.33 (m, 1H), 3.61-3.58 (m, 1H), 3.48-3.45 (m,1H), 3.27-3.13 (m, 3H), 2.77-2.65 (m, 2H), 1.41-1.37 (m, 6H), 1.34 (d,J=6.6 Hz, 3H).

Example 315

2-Isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (127 mg) was prepared as in Example 311 using 260 mgof2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester and 112 mg of 4-methylphenylboronic acid. Thereaction sequence also yielded2-isopropyl-5-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.MS (ESI): exact mass calculated for C₁₈H₂₅N₃, 283.20; found, m/z 284.5[M+H]⁺. ¹H NMR (600 MHz, CD₃OD): 7.38-7.36 (m, 2H), 7.22-7.20 (m, 2H),4.41 (m, 1H), 3.60-3.56 (m, 1H), 3.50-3.45 (m, 1H), 3.21-3.06 (m, 3H),2.84-2.70 (m, 2H), 1.46 (d, J=6.6 Hz, 3H), 1.42-1.37 (m, 6H).

Examples 316 through 323 were prepared as described in Example 238, withadjustments as noted.

Example 316

3-(4-Chloro-phenyl)-1-pyridin-4-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.02 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.3 mmol) using4-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₁₉H₁₉ClN₄, 338.13; found, m/z 339.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.49-8.48 (m, 2H), 7.43-7.41 (m, 2H), 7.33-7.31 (m, 2H), 6.90-6.89 (m,2H), 5.28 (s, 2H), 2.92-2.87 (m, 2H), 2.75-2.73 (m, 1H), 2.66-2.64 (m,1H).

Example 317

3-(4-Chloro-phenyl)-1-pyridin-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.01 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.4 mmol) using2-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of2-chloromethyl-thiophene. The reaction sequence also yielded3-(4-chloro-phenyl)-2-pyridin-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butylester in the alkylation step. MS (ESI): exact mass calculated forC₁₉H₁₉ClN₄, 338.13; found, m/z 339.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m,2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2.93-2.87 (m, 4H),2.76-2.74 (m, 4H).

Example 318

3-(4-Chloro-phenyl)-2-pyridin-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.011 g) was prepared from3-(4-chloro-phenyl)-2-pyridin-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butylester (Example 317) according to Example 103, Step C. MS (ESI): exactmass calculated for C₁₉H₁₉ClN₄, 338.13; found, m/z 339.3 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 8.44-8.43 (m, 1H), 7.56-7.55 (m, 1H), 7.32-7.27 (m,2H), 7.11-7.07 (m, 3H), 6.81-6.77 (m, 1H), 5.20 (s, 2H), 2.98-2.96 (m,2H), 2.89-2.86 (m, 4H), 2.48-2.46 (m, 2H).

10

Example 319

3-(4-Chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.3 mmol) using3-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of2-chloromethyl-thiophene. The title compound was obtained as a 2:1mixture (25 mg) with3-(4-chloro-phenyl)-2-pyridin-3-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.Data for the mixture: MS (ESI): exact mass calculated for C₁₉H₁₉ClN₄,338.13; found, m/z 339.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.47-8.14 (m,2H), 7.42-7.03 (m, 6H), 5.39-5.07 (two s, 2H), 2.97-2.84 (m, 2H),2.72-2.43 (m, 2H).

Example 320

4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzoicacid methyl ester

The title compound (0.03 g) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.3 mmol) using4-bromomethyl-benzoic acid methyl ester (0.5 mmol) in place of2-chloromethyl-thiophene. MS (ESI): exact mass calculated forC₂₂H₂₂ClN₃O₂, 395.14; found, m/z 396.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.63-7.19 (m, 7H), 7.03-7.02 (m, 2H), 5.27 (s, 2H), 3.15 (s, 2H),2.79-2.67 (m, 8H).

Example 321

3-(4-Chloro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.40 mmol) using4-chloro-tetrahydro-pyran (1.5 mmol) in place of chloro-cyclobutane. Thetitle compound was obtained as a 2:1 mixture (10 mg) with3-(4-chloro-phenyl)-2-(tetrahydro-pyran-4-yl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.Data for the mixture: MS (ESI): exact mass calculated for C₁₈H₂₂ClN₃O,331.15; found, m/z 332.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.44-7.42 (m,1H), 7.36-7.30 (m, 4H), 7.20-7.18 (m, 1H), 4.36-4.33 (m, 1H), 3.97-3.94(m, 3H), 3.87-3.86 (m, 1H), 3.51-3.49 (m, 3H), 3.28-3.25 (m, 1H),2.90-2.75 (m, 8H), 2.66-2.64 (m, 2H), 2.39-2.37 (m, 1H), 2.19-2.10 (m,3H), 1.74-1.71 (m, 2H), 1.65-1.62 (m, 1H).

Example 322

3-(4-Chloro-phenyl)-1-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (11 mg) was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.30 mmol) using1-bromo-4-methyl-cyclohexane (1.0 mmol) in place of chloro-cyclobutane.The reaction sequence also yielded3-(4-chloro-phenyl)-2-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₂₀H₂₆ClN₃, 343.18; found, m/z 344.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.40-7.34 (m, 4H), 4.10-4.06 (m, 1H), 3.39-3.37 (m, 2H),3.28-3.26 (m, 2H), 3.17-3.15 (m, 2H), 2.94-2.91 (m, 2H), 1.96-1.89 (m,2H), 1.83-1.76 (m, 4H), 1.52-1.10 (m, 2H), 0.91-0.87 (m, 4H).

Example 323

{2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]ethyl}-dimethyl-amine

The title compound was prepared from3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.33 mmol) using(2-chloro-ethyl)-dimethyl-amine hydrogen chloride (0.66 mmol) in placeof chloro-cyclobutane. The title compound was obtained as a 2:1 mixture(10 mg) with{2-[3-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-ethyl}-dimethyl-amine.Data for the mixture: MS (ESI): exact mass calculated for C₁₇H₂₃ClN₄,318.16; found, m/z 319.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.50-7.45 (m,2H), 7.37-7.33 (m, 2H), 4.51-4.49 (m, 1.3H), 4.27-4.26 (m, 0.7H),3.63-3.61 (m, 1.3H), 3.48-3.42 (m, 2H), 3.33-3.29 (m, 2H), 3.24-3.23 (m,2H), 3.14-3.12 (m, 0.7H), 3.00-2.98 (m, 1.3H), 2.91 (s, 4H), 2.84 (s,2H), 2.75-2.73 (m, 0.7H).

Example 324

3-(4-Chloro-phenyl)-1-(1-oxy-pyridin-2-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

A mixture of3-(4-chloro-phenyl)-2-pyridin-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 317; 0.1 mmol) and mCPBA (0.1 g) indichloroethane (10 mL) was heated at 80° C. for 1 h. Satd. aq. NaHCO₃(20 mL) was added, and the layers were separated. The organic layer wasconcentrated, and the residue was diluted with MeOH (5 mL). Hydrogenchloride (1 M, 2 mL) was added and the mixture was stirred at 25° C. for16 h. After concentration, purification by flash chromatography (2 MNH₃/MeOH in CH₂Cl₂) provided the desired compound (34 mg). MS (ESI):exact mass calculated for C₁₉H₁₉ClN₄O, 354.12; found, m/z 355.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 8.20-8.19 (m, 1H), 7.41-7.39 (m, 2H), 7.33-7.31(m, 2H), 7.18-7.15 (m, 2H), 6.69-6.67 (m, 1H), 5.50 (s, 2H), 3.10-3.03(m, 2H), 2.93-2.86 (m, 2H).

Example 325

2-[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetamide

A mixture of1-benzyl-3-(4-chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Example 59, Step E; 0.05 mmol), 2-bromo-acetamide (8 mg), and Na₂CO₃(15 mg) in acetone (2 mL) was stirred at 25° C. for 16 h. Afterconcentration, purification by flash chromatography (2 M NH₃/MeOH inCH₂Cl₂) provided the desired compound (6 mg). MS (ESI): exact masscalculated for C₂₂H₂₃ClN₄O, 394.16; found, m/z 395.3 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H),7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H),2.93-2.87 (m, 2H), 2.76-2.74 (m, 2H).

Example 326

3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-propionitrile

To a mixture of3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 103, Step B; 0.05 mmol), NaOH (50% aq.,0.2 mL), and Bu₄NHSO₄ (0.005 mmol) in dichloroethane (5 mL) was added3-bromo-propionitrile (0.1 mmol). The mixture was stirred at 25° C. for16 h and then was heated at 80° C. for 1 h. After concentration,purification by flash chromatography (EtOAc/hexanes) provided3-[3-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-propionitrile-6-carboxylicacid tert-butyl ester. Deprotection of this ester according to thedeprotection method in Example 103, Step C, gave the title compound (9mg). The reaction sequence also yielded3-[3-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-propionitrile-6-carboxylicacid tert-butyl ester in the alkylation step. MS (ESI): exact masscalculated for C₁₆H₁₇ClN₄, 300.11; found, m/z 301.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.44-7.37 (m, 4H), 4.39-4.37 (t, J=6.1 Hz, 2H), 3.41-3.39(m, 2H), 3.29-3.27 (m, 2H), 3.24-3.22 (m, 2H), 2.99-2.96 (m, 2H),2.95-2.92 (t, J=6.1 Hz, 2H).

Example 327

3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-propionitrile

The title compound (0.004 g) was prepared from3-[3-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-propionitrile-6-carboxylicacid tert-butyl ester (Example 326) according to the deprotection methodin Example 103, Step C. MS (ESI): exact mass calculated for C₁₆H₁₇ClN₄,300.11; found, m/z 301.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.50-7.48 (m,2H), 7.31-7.30 (m, 2H), 4.14-4.11 (t, J=6.1 Hz, 2H), 3.32-3.31 (m, 2H),3.23-3.21 (m, 2H), 3.09-3.07 (m, 2H), 2.86-2.84 (t, J=6.1 Hz, 2H),2.72-2.70 (m, 2H).

Example 328

3-(4-Chloro-phenyl)-2-cycloheptyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.010 g) was prepared from3-(4-chloro-phenyl)-2-cycloheptyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 254, Step C) according to thedeprotection method in Example 103, Step C. MS (ESI): exact masscalculated for C₂₀H₂₆ClN₃, 343.18; found, m/z 344.5 [M+H]⁺. ^(‘)H NMR(500 MHz, CD₃OD): 7.60-7.58 (m, 2H), 7.33-7.31 (m, 2H), 4.10-4.06 (m,1H), 3.41-3.39 (m, 2H), 3.31-3.29 (m, 2H), 3.18-3.16 (m, 2H), 2.78-2.75(m, 2H), 2.10-2.05 (m, 2H), 1.91-1.87 (m, 2H), 1.80-1.76 (m, 2H),1.60-1.58 (m, 4H), 1.40-1.39 (m, 2H).

Example 329

3-(4-Chloro-phenyl)-2-cyclooctyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.017 g) was prepared from3-(4-chloro-phenyl)-2-cyclooctyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 255, Step C) according to thedeprotection method in Example 103, Step C. MS (ESI): exact masscalculated for C₂₁ H₂₈ClN₃, 357.20; found, m/z 358.5 [M+H]⁺. ^(‘)H NMR(500 MHz, CD₃OD): 7.61-7.58 (m, 2H), 7.34-7.32 (m, 2H), 4.24-4.21 (m,1H), 3.41-3.39 (m, 2H), 3.31-3.29 (m, 2H), 3.18-3.16 (m, 2H), 2.78-2.76(m, 2H), 2.15-2.11 (m, 2H), 1.81-1.77 (m, 4H), 1.57-1.46 (m, 6H),1.31-1.29 (m, 2H).

Example 330

3-(4-Chloro-phenyl)-2-(4-methyl-cyclohexyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound (0.007 g) was prepared from3-(4-chloro-phenyl)-2-(4-methyl-cyclohexyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester (Example 322, Step C) according to thedeprotection method in Example 103, Step C. MS (ESI): exact masscalculated for C₂₀H₂₆ClN₃, 343.18; found, m/z 344.4 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): 7.59-7.57 (m, 2H), 7.33-7.31 (m, 2H), 3.95-3.92 (m, 1H),3.37-3.35 (m, 2H), 3.31-3.29 (m, 2H), 3.18-3.16 (m, 2H), 2.78-2.75 (m,2H), 2.10-1.95 (m, 2H), 1.90-1.77 (m, 4H), 1.05-0.91 (m, 6H),

Example 331

2-Benzyl-3-(4-chloro-phenyl)-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole

To a solution of LDA (1.80 M in THF, 20 mmol) in THF (100 mL) at −78°C., was added a solution of 3-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (10 mmol) in THF (10 mL) dropwise. After 20 min, asolution of 4-chlorobenzyl chloride (15 mmol) in THF (10 mL) was added.Then the mixture was warmed to 25° C. and stirred for 16 h. Satd. aq.NaHCO₃ (100 mL) was added, and the organic layer was separated andconcentrated to give 3-(4-chloro-benzyl)-4-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester. This residue (⅛ portion, approx. 1.25 mmol) wasdiluted with EtOH (10 mL) and treated with benzyl hydrazine hydrogenchloride (1.5 mmol) and K₂CO₃ (5 mmol). The mixture was stirred at 25°C. for 16 h. Concentration and purification by flash chromatography(EtOAc/CH₂Cl₂) provided2-benzyl-3-(4-chloro-phenyl)-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylicacid tert-butyl ester. A solution of the ester and TFA (2 mL) in CH₂Cl₂(10 mL) was stirred at 25° C. for 4 h. Concentration and purification byflash chromatography (2 M NH₃ in MeOH/CH₂Cl₂) provided the desiredcompound (10 mg). MS (ESI): exact mass calculated for C₁₈H₁₆ClN₃,309.10; found, m/z 310.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.37-7.21 (m,7H), 7.08-7.05 (m, 2H), 5.29 (s, 2H), 4.09 (s, 2H), 4.04 (s, 2H).

Example 332

1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.017 g), as a hydrochloride salt, was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.15 g) using 4-chlorobenzylbromide (0.1 g) in place of benzyl chloride in Example 59, Step D. MS(ESI): exact mass calculated for C₂₀H₁₉Cl₂N₃, 371.10; found, m/z 372.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.57-7.50 (m, 4H), 7.41-7.33 (m, 2H),7.27-7.19 (m, 2H), 5.45 (s, 2H), 4.34 (s, 2H), 3.57-3.53 (m, 2H),3.08-3.03 (m, 2H), 2.08-2.02 (m, 2H).

Example 333

3-(4-Chloro-phenyl)-1-(4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.011 g), as a hydrochloride salt, was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.15 g) using 4-methylbenzylbromide (0.09 g) in place of benzyl chloride in Example 59, Step D. MS(ESI): exact mass calculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.46-7.39 (m, 2H), 7.21-7.18 (m, 2H),6.98-6.95 (m, 2H), 6.77-6.74 (m, 2H), 5.08 (s, 2H), 3.97 (s, 2H),3.46-3.43 (m, 2H), 2.96-2.92 (m, 2H), 2.17 (s, 3H), 2.01-1.97 (m, 2H).

Example 334

3-(4-Chloro-phenyl)-1-(3,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.005 g) was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.07 g) using3,4-difluorobenzyl bromide (0.06 g) in place of benzyl chloride inExample 59, Step D. MS (ESI): exact mass calculated for C₂₀H₁₈ClF₂N₃,373.12; found, m/z 374.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.39-7.34 (m,4H), 7.16-7.10 (m, 1H), 6.98-6.97 (m, 1H), 6.89-6.88 (m, 1H), 5.27 (s,2H), 3.81 (s, 2H), 3.09-3.06 (m, 2H), 2.80-2.76 (m, 2H), 1.75-1.70 (m,2H).

Example 335

3-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.012 g) was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-methylbenzylbromide (0.06 g) in place of benzyl chloride in Example 59, Step D. MS(ESI): exact mass calculated for C₂₁H₂₂ClN₃, 351.15; found, m/z 352.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.49-7.43 (m, 4H), 7.19 (t, J=7.6 Hz,1H), 7.08 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 5.34(s, 2H), 3.88 (s, 2H), 3.16-3.13 (m, 2H), 2.88-2.85 (m, 2H), 2.30 (s,3H), 1.80-1.77 (m, 2H).

Example 336

3-(4-Chloro-phenyl)-1-(3-fluoro-4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.002 g) was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using3-fluoro-4-methylbenzyl bromide (0.09 g) in place of benzyl chloride inExample 59, Step D. MS (ESI): exact mass calculated for C₂₁H₂₁ClFN₃,369.14; found, m/z 370.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.49-7.43 (m,4H), 7.19 (t, J=7.9 Hz, 1H), 6.88-6.80 (m, 2H), 5.34 (s, 2H), 3.88 (s,2H), 3.16-3.13 (m, 2H), 2.87-2.85 (m, 2H), 2.23 (d, J=1.5 Hz, 3H),1.81-1.78 (m, 2H).

Example 337

3-(4-Chloro-phenyl)-1-(4-fluoro-3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene

The title compound (0.001 g) was prepared from3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylicacid tert-butyl ester (Example 59, Step C; 0.1 g) using4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride inExample 59, Step D. MS (ESI): exact mass calculated for C₂₁H₂₁ClFN₃,369.14; found, m/z 370.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.48-7.43 (m,4H), 7.08-7.06 (m, 1H), 6.99-6.97 (m, 2H), 5.32 (s, 2H), 3.88 (s, 2H),3.16-3.14 (m, 2H), 2.89-2.86 (m, 2H), 2.22 (d, J=1.6 Hz, 3H), 1.80 (m,2H).

Example 338

3-(4-Fluoro-phenyl)-2-isopropyl-5,7-dimethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

The title compound was prepared in a manner analogous to those describedabove.

Assay Methods

In vitro pharmacology

1. Affinity for 5-HT₇ Receptor Binding Sites

The affinity of the compounds described in this invention for the 5-HT₇receptor binding site was evaluated by single competition radioligandbinding assay. The assay was performed on membranes prepared fromHEK-293 cells that had been subjected to stable transfection with therat 5-HT_(7a) receptor (GB: NM022938). Cells were scraped from theculture plates, suspended in Tris-HCl 50 mM pH 7.5 and collected throughcentrifugation (1000 rpm for 5 min). The cell pellets were homogenized(Polytron, 15 s, setting 5) in 50 mM Tris-HCl (pH 7.5), 5 mM EDTA.Following centrifugation (15,000 rpm for 25 min), membranes (135 μgprotein/mL) were resuspended in the same buffer and incubated for 60 minat RT with 1 nM [³H]5-CT in the presence of increasing concentration oftest compounds. Nonspecific binding was defined in the presence of 10 μM5-HT. Incubation was stopped by rapid filtration using the cellharvester (Packard). Radioactivity was counted in a TopCount-NXT(Packard).

Sigmoidal inhibition curves were generated and fitted by nonlinearregression analysis (GraphPad Prism). IC₅₀ values (concentrationproducing 50% inhibition of specific radioligand binding) werecalculated. K, values were derived according to Cheng and Prussoff(Biochem. Pharmacol. (1973) 22: 3099-3108). Experiments were conductedin triplicate.

Stock drug solutions (10 mM) were prepared in DMSO (the final assayconcentration of DMSO not exceeding 0.4%). Drug dilutions were preparedin assay buffer. Data are shown in Table 1 below.

2. Effect on Adenylyl Cyclase Activity

In vitro functional properties of the compounds described in thisinvention were evaluated in an adenylyl cyclase assay. HEK-293 cellsstably tranfected with the rat 5-HT_(7a) receptor were plated into96-well plates. Cells were washed with 200 μL DNEM/F12 and incubated for10 min with 80 μL of 2 mM 3-isobutyl-1-methylxanthine. Compounds (10 μL)were added for another 10 min. Subsequently, 5-CT (10 μL) was added.After 20 min the incubation was stopped by the addition of 20 μL of 0.5N HCl. Plates were incubated at 4° C. for 30 min. Twenty μL of thesupernatant were assayed for cAMP content with a commercially availablekit (Perkin Elmer) using ¹²⁵I-cAMP. Sigmoidal curves of best fit werecalculated by nonlinear regression analysis using GrapPad Prism.

5-CT-stimulated adenylyl cyclase activity in r5-HT_(7a)/HEK-293 cellswas inhibited by Example 59 with an estimated pK_(B)˜8 in good agreementwith the K_(i) value determined from [³H]5-CT binding studies.

3. Affinity for 5-HT_(2A) Receptor Binding Sites

The affinity of the compounds for the rat 5-HT_(2A) receptor wasevaluated by competitive radioligand binding assay using [³H]ketanserineas the radioligand. The assay was performed on membranes from rat cortexas previously described (Schotte, A. et al., Psychopharmacology (1996)124: 57-73). Briefly, brain tissue (rat cortex) was homogenized in 20volumes per wet weight tissue of Tris-HCl buffer (50 mM, pH 7.4). Thetotal membrane fraction was collected by centrifugation and washed bysubsequent centrifugation runs (25 min at 25,000 g at 4° C.). Membraneswere re-suspended in Tris-HCl buffer (50 mM, pH 7.4) containing 1 nM[³H]ketanserin. Non-specific binding was estimated in the presence of 10μM risperidone. The incubation was terminated by rapid filtration overWhatman GF/B filters pre-soaked in 0.1% polyethylenimine, and onewashing step with 1 mL ice-cold Tris-HCl buffer, pH 7.4. pK_(i) valuesfor all compounds were calculated by pK_(i)=−log K_(i) where K_(i) wascalculated according to the method of Cheng and Prusoff (BiochemPharmacol. (1973) 22: 3099-3108) (IC₅₀/(1+[S]/K_(d)) were [S]=1 nM;K_(d)=0.42 nM). All values in Table 1 are listed in nM units. Data areshown in Table 1 below.

4. Affinity for 5HT2 Receptor Binding Sites

Receptor binding was performed using the human recombinant 5-HT_(2A)(GB: X57830), 5-HT_(2B) (GB: Z36748) and 5-HT_(2c) (GB: M81778)receptors. The affinity of the compounds for the 3 different human 5-HT₂receptor subtypes was evaluated by competitive radioligand bindingassays using [³H]ketanserin (h5-HT_(2A)) or [³H]mesulergine (h5-HT_(2B)and h5-HT_(2c)). The assays were performed on membranes prepared fromNIH3T3 stably transfected with h5-HT_(2A) or CHO stably transfected withh5-HT_(2B) and h5-HT_(2C). K_(i) values for all compounds werecalculated according to Cheng and Prusoff equation (Cheng and Prusoff,Biochem. Pharmacol. (1973)22:3099-3108) (IC₅₀/(1+[S]/K_(d)) where [S]=1nM (5-HT_(2A)), 4 nM (5-HT_(2B)) and 3 nM (5-HT_(2C)); K_(d)=0.4 nM(5-HT_(2A)), 3.5 nM (5-HT_(2B)) and 3 nM (5-HT_(2C)). Data are shown inTable 1 below.

5. In Vitro Functional Assay for 5-HT2 Receptor (Intracellular Calcium)

In vitro functional properties of these compounds on the different 5-HT₂receptor subtypes were determined using fluorometric imaging platereader (FLIPR) based calcium assay as previously described (Porter etal., 1999, Jerman, J. C. et al. Eur. J. Pharmacol. (2001)414:23-30). The5-HT₂ receptors are linked to the Gq family of G proteins and tosubsequent activation of phospholipase C, induction of phosphoinositidemetabolism and to an increase in intracellular calcium concentration.The same cell lines as described in the previous section (receptorbinding) were used for the FLIPR experiments.

TABLE 1 Binding Affinities (nM) K_(i) K_(i) K_(i) K_(i) EX 5-HT₇5-HT_(2A) 5-HT_(2B) 5-HT_(2C) 1 120 NT NT NT 17 70 NT NT NT 18 25 NT NTNT 22 45 NT NT NT 26 18 NT NT NT 38 pK_(b) 7.8 NT NT NT 47 7 9 64 24 5715 NT NT NT 59 6 280 160 74 64 19 18 NT NT 74 5 100 94 180 75 7 200 100320 76 8 210 350 690 87 33 NT NT NT 98 40 NT NT NT 100 30 NT NT NT 1037.7 60 44 150 104 9 80 52 360 108 9 NT 100 800 111 17 NT NT NT 114 32 NT90 400 117 20 NT NT NT 118 8 20 NT NT 119 39 NT NT NT 120 40 NT NT NT131 120 7 4.2 50 133 125 2.3 3.5 10 160 7 300 350 3500 165 4 100 310 180166 8 80 560 590 167 75 NT 350 10000 172 37 NT NT NT 174 40 NT NT NT 17780 7 7 110 178 85 3 3 NT 180 10 1.5 1.4 12 181 37 1.5 1.8 11 182 90 0.741.4 18 183 240 7 54 70 184 120 1 17 15 186 61 1 24 20 190 16 10 22 51191 30 NT NT NT 192 20 2.5 0.9 15 209 6 1.1 1.4 12 210 7 2 0.75 20 2118.5 5 0.5 18 212 93 25 12 425 213 12 7.5 4.7 80 214 5 NT 2 170 215 30 895 NT 216 70 6 20 17 217 25 1 0.65 10 218 75 1.7 1.8 15 220 55 1.3 0.556.8 232 20 25 0.50 66 233 15 4 25 16 236 950 7 4.5 32 238 40 1 0.50 13241 310 9 9.5 38 242 21 8 1.3 45 253 75 NT 25 625 255 60 NT NT NT 257 9NT 2 110 273 5 400 NT NT 276 90 3 2.5 90 277 150 0.9 3 40 278 35 0.1 0.210 279 80 0.8 1 45 280 3300 1.5 6 120 282 100 6 20 200 283 5000 10 60150 284 10 1 2 60 285 29 60 6 500 286 335 50 80 5000 298 50 5 6.5 60 29935 1.7 9 26 300 10 0.3 0.8 12 301 40 1.6 3 100 302 100 0.2 1.3 21.5 305600 20 60 2200 306 120 1 22 39 308 5200 2 3 162 309 130 30 15 130 310475 0.2 0.4 30 311 80 140 100 3000 313 30 100 40 1000 315 12 9 3 300 3169.1 60 530 5000 NT = not tested

1. A compound having of formula (III):

wherein m is 0, 1 or 2; n is 1, 2 or 3; m+n is 2 or 3; q is 0 when CYCis other than hydrogen, or 1; r is 0, 1 or; R³ is —C₁₋₄alkyl; Ar is anaryl or heteroaryl ring selected from the group consisting of: a)phenyl, optionally mono-, di- or tri-substituted with R^(r) ordi-substituted on adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(r) is selected from the group consisting of —OH,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₂₋₆alkenyl, —OC₃₋₆alkenyl, —C₂₋₆alkynyl,—OC₃₋₆alkynyl, —CN, —NO₂, —N(R³)R^(z) (wherein R^(y) and R^(z) areindependently selected from H or C₁₋₆alkyl), —(C═O)N(R³)R^(z),—(N—R^(t))COR^(t), —(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t) is H orC₁₋₆alkyl), —(C═O)C₁₋₆alkyl, —(S═(O)_(n)—C₁₋₆alkyl (wherein n isselected from 0, 1 or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo, —CF₃, —OCF₃,—COOH and —COOC₁₋₆alkyl; b) phenyl or pyridyl fused at two adjacentcarbon ring members to a three membered hydrocarbon moiety to form afused five membered aromatic ring, which moiety has one carbon atomreplaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up to oneadditional carbon atom optionally replaced by —N═, the fused ringsoptionally mono-, di- or tri-substituted with R^(r); c) phenyl fused attwo adjacent ring members to a four membered hydrocarbon moiety to forma fused six membered aromatic ring, which moiety has one or two carbonatoms replaced by —N═, the fused rings optionally mono-, di- ortri-substituted with R^(r); d) naphthyl, optionally mono-, di- ortri-substituted with R^(r); e) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(r) andoptionally benzofused or pyridofused at two adjacent carbon atoms, wherethe benzofused or pyridofused moiety is optionally mono-, di-, ortri-substituted with R^(r); and f) a monocyclic aromatic hydrocarbongroup having six ring atoms, having a carbon atom which is the point ofattachment, having one or two carbon atoms replaced by —N═, optionallymono- or di-substituted with R^(r) and optionally benzofused orpyridofused at two adjacent carbon atoms, where the benzofused orpyridofused moiety is optionally mono- or di-substituted with R^(r); g)phenyl or pyridyl, substituted with a substituent selected from thegroup consisting of phenyl, pyridyl, thiophenyl, oxazolyl andtetrazolyl, where the resultant substituted moiety is optionally furthermono-, di- or tri-substituted with R^(I.); ALK is a branched orunbranched C₁₋₈alkylene, C₂₋₈alkenylene, C₂₋₈alkynylene orC₃₋₈cycloalkenylene, optionally mono-, di-, or tri-substituted with asubstituent independently selected from the group consisting of: —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂, —N(R^(a))R^(b) (wherein R^(a)and R^(b) are independently selected from H, C₁₋₆alkyl or C₂₋₆alkenyl),—(C═O)N(R^(a))R^(b), —(N—R^(c))COR^(c), —(N—R^(c))SO₂C₁₋₆ alkyl (whereinR^(c) is H or C₁₋₆alkyl), —(C═O)C₁₋₆alkyl, —(S═(O)_(d))—C₁₋₆alkyl(wherein d is selected from 0, 1 or 2), —SO₂N(R^(a))R^(b), —SCF₃, halo,—CF₃, —OCF₃, —COOH and —COOC₁₋₆alkyl; CYC is hydrogen or a carbocyclic,heterocyclic, aryl or heteroaryl ring selected from the group consistingof: i) phenyl, optionally mono-, di- or tri-substituted with R^(q) ordi-substituted on adjacent carbons with —OC₁₋₄ alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄ alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(q) is selected from the group consisting of —OH,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, phenyl,—Ophenyl, benzyl, —Obenzyl, —CN, —NO₂, —N(R^(a))R^(b) (wherein R^(a) andR^(b) are independently selected from H, C₁₋₆alkyl or C₂₋₆alkenyl, orR^(a) and R^(b) may be taken together with the nitrogen of attachment toform an otherwise aliphatic hydrocarbon ring, said ring having 5 to 7members, optionally having one carbon replaced with >O, ═N—, >NH or>N(C₁₋₄alkyl), optionally having one carbon substituted with —OH, andoptionally having one or two unsaturated bonds in the ring),—(C═O)N(R^(a))R^(b), —(N—R^(c))COR^(c), —(N—R^(c))SO₂C₁₋₆alkyl (whereinR^(c) is H or C₁₋₆alkyl or two R^(c) in the same substituent may betaken together with the amide of attachment to form an otherwisealiphatic hydrocarbon ring, said ring having 4 to 6 members),—N—(SO₂C₁₋₆alkyl)₂, —(C═O)C₁₋₆alkyl, —(S═(O)_(d))—C₁₋₆alkyl (wherein dis selected from 0, 1 or 2), —SO₂N(R^(a))R^(b), —SCF₃, halo, —CF₃,—OCF₃, —COOH and —COOC₁₋₆alkyl; ii) phenyl or pyridyl fused at twoadjacent carbon ring members to a three membered hydrocarbon moiety toform a fused five membered aromatic ring, which moiety has one carbonatom replaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up toone additional carbon atom optionally replaced by —N═, the fused ringsoptionally mono-, di- or tri-substituted with R^(q); iii) phenyl fusedat two adjacent carbon ring members to a four membered hydrocarbonmoiety to form a fused six membered aromatic ring, which moiety has oneor two carbon atoms replaced by —N═, the fused rings optionally mono-,di- or tri-substituted with R^(q); iv) naphthyl, optionally mono-, di-or tri-substituted with R^(q); v) a monocyclic aromatic hydrocarbongroup having five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(q) andoptionally benzofused or pyridofused at two adjacent carbon atoms, wherethe benzofused or pyridofused moiety is optionally mono-, di-, ortri-substituted with R^(q); vi) a monocyclic aromatic hydrocarbon grouphaving six ring atoms, having a carbon atom which is the point ofattachment, having one or two carbon atoms replaced by —N═, optionallymono- or di-substituted with R^(q) and optionally benzofused orpyridofused at two adjacent carbon atoms, where the benzofused orpyridofused moiety is optionally mono- or di-substituted with R^(q);vii) a 3-8 membered non-aromatic carbocyclic or heterocyclic ring saidring having 0, 1 or 2 non-adjacent heteroatom members selected from O,S, —N═, >NH or >NR^(q), having 0, 1 or 2 unsaturated bonds, having 0, 1or 2 carbon members which is a carbonyl, optionally having one carbonmember which forms a bridge, having 0 to 5 substituents R^(q) andoptionally benzofused or pyridofused at two adjacent carbon atoms wherethe benzofused or pyridofused moiety has 0, 1, 2 or 3 substituentsR^(q); and viii) a 4-7 membered non-aromatic carbocyclic or heterocyclicring said ring having 0, 1 or 2 non-adjacent heteroatom members selectedfrom O, S, —N═, >NH or >NR^(q), having 0, 1 or 2 unsaturated bonds,having 0, 1 or 2 carbon members which is a carbonyl and optionallyhaving one carbon member which forms a bridge, the heterocyclic ringfused at two adjacent carbon atoms forming a saturated bond or anadjacent carbon and nitrogen atom forming a saturated bond to a 4-7membered carbocyclic or heterocyclic ring, having 0 or 1 possiblyadditional heteroatom member, not at the ring junction, selected from O,S, —N═, >NH or >NR’, having 0, 1 or 2 unsaturated bonds, having 0, 1 or2 carbon members which is a carbonyl and the fused rings having 0 to 5substituents R^(q); R¹ is and enantiomers, diastereomers, hydrates,solvates and pharmaceutically acceptable salts, esters and amidesthereof.
 2. The compound of claim 1 wherein m is 1 or
 2. 3. The compoundof claim 1 wherein m is
 1. 4. The compound of claim 1 wherein n is 1 or2.
 5. (canceled)
 6. The compound of claim 1 wherein m+n is
 2. 7.(canceled)
 8. The compound of claim 1 wherein q is
 1. 9. The compound ofclaim 1 wherein r is
 0. 10. (canceled)
 11. The compound of claim 1wherein R³, optionally substituted, is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl and butyl.
 12. Thecompound of claim 1 wherein R³ is methyl.
 13. The compound of claim 1wherein Ar, optionally substituted, is selected from the groupconsisting of: a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl, b) 4-, 5-, 6- or7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl,4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5, 6 or7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4,6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, c) 5-, 6-, 7- or 8-isoquinolinyl,5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or8-quinazolinyl, d) naphthyl, e) furanyl, oxazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2- or3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl, f) pyridinyl,pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3- or4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2- or 3-quinoxalinyl, 2- or4-quinazolinyl, [1,5], [1,6], [1,7], or [1,8]naphthyridin-2-, 3-, or4-yl, [2,5], [2,6], [2,7], [2,8]naphthyridin-1-, 3-, or 4-yl, and g)biphenyl, 4-tetrazolylphenyl.
 14. The compound of claim 1 wherein Ar,optionally substituted, is selected from the group consisting of phenyl,pyridyl, thiophen-2-yl and thiophen-3-yl.
 15. The compound of claim 1wherein Ar is selected from the group consisting of phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl,4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxo1-4 or5-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl,4-dimethylaminophenyl,4-carbamoylphenyl, 4-fluoro-3-methylphenyl, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl,5-methylthiophen-2-yl, 5-chlorothiophen-3-yl, 5-methylthiophen-3-yl,4′-chlorobiphenyl, and 4-tetrazolylphenyl.
 16. The compound of claim 1wherein ALK, optionally substituted, is selected from the groupconsisting of methylene, ethylene, propylene, butylene, tert-butylene,pentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene,isopropylene, but-3-enylene, isobutylene, 3-methylbutylene, allylene,and prop-2-ynylene.
 17. The compound of claim 1 wherein ALK is selectedfrom the group consisting of methylene, trifluoromethylmethylene,methoxycarbonylmethyl, methylcarbamoylmethyl, ethylene, propylene,3-methoxycarbonyl propylene, 3-carboxy propylene, butylene,tert-butylene, 4-hydroxybutylene, 4-methoxycarbonyl butylene, 4-carboxybutylene, pentylene, 5-hydroxypentylene, 1-ethylpropylene,2-ethylpropylene, 2-ethylbutylene, isopropylene, but-3-enylene,isobutylene, 3-methylbutylene, prop-2-ynylene, 2-dimethylaminoethylene,and 2-cyanoethylene.
 18. The compound of claim 1 wherein CYC, optionallysubstituted, is hydrogen or is selected from the group consisting of: i)phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl, ii) 4-, 5-, 6- or7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl,4-, 5-, 6or 7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5, 6 or7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4,6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, iii) 5-, 6-, 7- or8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl, iv) naphthyl, v) furanyl,oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl,2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl,2-benzimidazolyl, 3-indazolyl, vi) pyridinyl, pyridinyl-N-oxide,pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3-or 4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5],[1,6], [1,7], or [1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6], [2,7],[2,8]naphthyridin-1-, 3-, or 4-yl, vii) cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,adamantyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, piperidinyl,homopiperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl,piperazinyl, morpholinyl, thiomorpholinyl, piperidinonyl, indanyl,dihydroindolyl, oxindolyl, dihydropyrrolopyridinyl, and viii)bicyclo[4.1.0]heptane, octahydroindolyl, octahydroisoindolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydropyrrolopyridinyl,and octahydropyrrolopyrrolidinyl.
 19. The compound of claim 1 whereinCYC, optionally substituted, is selected from the group consisting ofhydrogen, phenyl, indolyl, benzthiazolyl, isoquinolyl, quinazolinyl,naphthalen-1 or 2-yl, thiophen-2-yl, thiophen-3-yl, furan-2-yl,furan-3-yl, pyridinyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, piperidin-2,3 or 4-yl, 2-pyrrolin-2, 3, 4 or 5-yl,3-pyrrolin-2 or 3-yl, 2-pyrazolin-3, 4 or 5-yl, morpholin-2, 3, 5 or6-yl, thiomorpholin-2, 3, 5 or 6-yl, piperazin-2, 3, 5 or 6-yl,pyrrolidin-2 or 3-yl, homopiperidinyl, adamantanyl, andoctahydroindolyl.
 20. The compound of claim 1 wherein CYC, optionallysubstituted, is selected from the group consisting of hydrogen, phenyl,pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, thiophen-2-yl,thiophen-3-yl, tetrahydropyranyl, furan-2-yl, furan-3-yl andnaphthalen-1 or 2-yl.
 21. The compound of claim 1 wherein CYC isselected from the group consisting of hydrogen, phenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl,cyclobutyl, cyclohexyl, cyclopentyl, 4-fluoro-3-methylphenyl,3-nitrophenyl, 4-nitrophenyl, 4-methyl-3-fluorophenyl,3,4-dimethylphenyl, 4-methoxy-3-fluorophenyl, 4-methoxy-2-methylphenyl,3-aminophenyl, 4-aminophenyl, 4-carbomethoxyphenyl,3-methanesulfonylamino-phenyl, 4-methanesulfonylamino-phenyl,3-dimethanesulfonylamino-phenyl, 4-dimethanesulfonylamino-phenyl,thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, benzo[1,3]dioxol-4or 5-yl, tetrahydropyran-2,3 or 4-yl, furan-2-yl, furan-3-yl,5-carboxyethyl-furan-2-yl, naphthalen-1 or 2-yl, 3,4-bisbenzyloxyphenyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl and3,4-dihydroxyphenyl. 22-28. (canceled)
 29. The compound of claim 1selected from the group consisting of:3-(4-Chloro-phenyl)-2-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-propyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Butyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2-cyclohexyl-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoicacid methyl ester;5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoicacid;5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentan-1-ol;4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyricacid methyl ester;4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butyricacid;4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-butan-1-ol;3-(4-Chloro-phenyl)-2-(3,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(4-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-cyclohexylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-furan-2-carboxylicacid ethyl ester;3-(4-Chloro-phenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-thiophen-2-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2,6-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2-ethyl-butyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-pentafluorophenylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-naphthalen-1-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(3,4-Bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-2-fluoro-phenol;4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-3-methyl-phenol;2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-phenol;2,3-Diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclohexyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(1-Ethyl-propyl)-3-(3-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(1-Ethyl-propyl)-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(1-Ethyl-propyl)-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(1-Ethyl-propyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(2,2,2-Trifluoro-ethyl)-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(1-Ethyl-propyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(3-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(3-Fluoro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(2-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Phenyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Fluoro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(3-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Phenyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2,3-Diphenyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine;3-Phenyl-2-(3-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Methoxy-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(4-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Ethyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;2-Isopropyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-tert-Butyl-3-phenyl-2,4,5,6,7, 8-hexahydro-1,2,6-triaza-azulene;2-tert-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-p-tolyl-2,4,5,6,7, 8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(3-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(3,3-Dimethyl-cyclopentyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(3,3-Dimethyl-cyclopentyl)-3-(4-fluoro-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(3,3-dimethyl-cyclopentyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclohexyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclohexyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclohexyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclohexyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;3-(3-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine;2-Cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-tert-Butyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-tert-Butyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-tert-Butyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(3-Chloro-4-fluoro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-(4-trifluoromethoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-tert-Butyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-m-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(3,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Benzyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(2-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;1-[4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-ethanone;2-Isopropyl-3-(4-nitro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene;2-Ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;2-Ethyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(2-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Ethyl-3-(2-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(2,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;[4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-dimethyl-amine;3-(4′-Chloro-biphenyl-4-yl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4′-Chloro-biphenyl-4-yl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclobutyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclobutyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile2-Cyclopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopropyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-(1-Ethyl-propyl)-3-(4-fluoro-3-methyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopropyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Cyclopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;2-Isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;3-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;2-Isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;2-sec-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-sec-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-sec-Butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzamide;2-Isopropyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Fluoro-phenyl)-2-isopropyl-4-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-(4-fluoro-phenyl)-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-7-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-pyridin-2-ylmethyl-1₅4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-propionitrile;3-(4-Chloro-phenyl)-2-cycloheptyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-cyclooctyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-(4-methyl-cyclohexyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;and3-(4-Fluoro-phenyl)-2-isopropyl-5,7-dimethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.30-31. (canceled)
 32. The compound of claim 1 selected from the groupconsisting of:3-(4-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Ethyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;3-(4-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;2-Isopropyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;2-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and2-Isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.33. (canceled)
 34. The compound of claim 1 wherein said pharmaceuticallyacceptable salt is selected from the group consisting of hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactiobionate, andlaurylsulfonate. 35-48. (canceled)